CRC Croce Tili List of patients for mir125b Metabolomic study Clinical data update 13/01/12

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1 AGGRESSIVE CRC Croce Tili List of patients for mir125b Metabolomic study Clinical data update 13/01/12 INDOLENT Table S1. Clinical data of the patients used for the study ID ZAP %VH WBC Dx date First TX if No Tx Last FU Last Sample Date Latest FollowUp DaDate of Death ID ZAP %VH WBC Dx date First TX if No Tx Last FU Last Sample Date Latest FollDate of Death 1 JCB /05/01 01/01/05 22/11/10 22/11/10 1 TJK /09/07 18/01/11 25/10/11 25/10/11 2 JCB /02/00 01/08/03 22/02/11 21/02/09 2 TJK /01/95 30/08/11 16/11/07 04/01/11 3 TJK /05/05 04/01/07 29/02/12 29/02/12 3 JGG /02/94 29/09/11 29/03/12 29/09/11 4 TJK /10/03 05/02/07 20/12/11 20/12/11 4 JGG /07/99 01/04/10 28/07/11 22/09/11 5 TJK /11/03 09/07/06 01/07/08 28/09/08 28/09/08 5 TJK /02/92 17/05/04 10/08/09 10/08/09 6 MJK /12/05 05/02/07 29/01/07 29/01/07 6 MJK /12/87 13/07/10 26/01/04 13/07/10 13/07/10 7 TJK /01/02 13/12/06 29/04/08 11/12/11 11/12/11 7 TJK /09/00 18/05/10 31/01/12 31/01/12 8 TJK /01/02 13/04/08 02/11/10 11/02/11 11/02/11 8 TJK /11/98 17/06/08 17/06/08 17/06/08 9 TJK /08/05 10/06/08 27/03/12 28/12/11 9 TJK /06/07 03/05/11 01/11/11 01/11/11 10 TJK /08/04 03/03/08 18/01/12 18/01/12 10 TJK /03/05 01/03/11 06/03/12 06/03/12 11 TJK /01/06 12/06/07 02/01/08 03/09/09 03/09/09 11 MJK /09/98 30/06/10 30/06/10 30/06/10 12 TJK /01/07 14/01/08 14/02/12 14/02/12 12 TJK /01/97 04/01/11 20/12/11 20/12/11 13 TJK /06/07 16/11/10 30/11/11 30/11/11 13 KRR /01/02 02/11/10 23/09/08 02/11/10 14 MJK /01/03 22/05/06 22/05/06 22/05/06 14 TJK /12/03 17/06/08 01/11/11 01/11/11 15 MJK ND 15/06/01 10/05/06 09/05/06 09/05/06 15 TJK /09/95 22/02/11 06/03/12 06/03/12 16 MJK /12/05 25/06/07 25/06/07 25/06/07 16 TJK /12/97 01/02/11 15/12/11 15/12/11 17 JGG /06/97 23/01/01 22/01/01 22/01/01 17 TJK /01/00 13/04/10 29/07/11 22/11/11 18 MJK /01/98 01/07/02 27/02/02 27/02/02 18 TJK /11/01 01/11/10 01/11/10 01/11/10 19 MJK /11/01 10/07/06 11/07/05 11/07/05 19 TJK /01/06 30/11/10 24/01/12 24/01/12 20 MJK /03/96 14/09/05 13/09/05 10/10/06 10/10/06 20 TJK /01/98 09/03/10 31/01/12 31/01/12 21 JCB /06/99 31/01/97 04/05/09 11/04/11 21 JCB /05/02 19/07/06 25/08/03 19/07/06 19/07/06 22 JCB /01/95 01/01/95 21/09/04 29/11/04 29/11/04 22 JGG /07/99 31/01/11 28/07/11 22/09/11 23 JCB /04/98 31/03/09 31/03/09 17/08/09 17/08/09 23 JGG /03/02 25/06/02 24/06/02 25/06/02 24 JRB /02/05 15/10/07 04/10/11 04/10/11 24 KRR NA 15/10/03 10/07/03 14/07/03 25 KRR /01/00 15/09/10 15/09/10 15/09/10 25 KRR /07/99 29/04/11 28/07/10 29/04/11 26 KRR /01/98 29/03/06 29/03/06 29/03/06 26 KRR /09/98 11/06/08 11/06/08 11/06/08 27 KRR /01/04 28/01/08 03/01/08 03/01/08 27 KRR /04/04 03/03/11 03/03/11 03/03/11 28 KRR ND /04/03 15/02/09 19/02/08 19/02/08 28 KRR /05/04 29/01/08 29/01/08 29/01/08 29 KRR /03/06 22/04/08 22/04/08 02/08/11 29 KRR /07/03 16/04/09 16/04/09 16/04/09 30 MJK /07/99 06/07/05 05/07/05 22/10/05 22/10/05 30 MJK /06/94 06/10/00 05/10/00 05/10/00 31 MJK /03/04 20/10/05 12/10/05 06/07/06 06/07/06 31 MJK /04/97 10/04/01 10/04/01 10/04/01 32 MJK /11/01 17/04/06 23/03/06 06/07/07 06/07/07 32 MJK /01/05 15/11/05 21/11/05 22/11/05 33 MJK /10/02 18/07/06 17/07/06 16/10/06 33 MJK0940 LA /06/97 30/01/06 30/01/06 30/01/06 34 NEK /08/01 20/09/01 15/02/06 29/02/08 29/02/08 34 MJK /10/00 04/05/06 11/04/06 11/04/06 35 TJK /12/03 01/01/07 29/12/08 29/03/09 29/03/09 35 TJK /05/97 07/09/05 14/12/11 14/12/11 36 TJK /09/03 01/01/04 02/05/06 02/05/06 36 TJK /03/97 20/04/99 19/08/99 20/04/99 37 TJK /09/03 01/01/04 02/05/06 02/05/06 37 TJK /01/07 07/07/10 20/03/12 20/03/12 38 TJK /10/02 01/02/11 07/02/12 07/02/12 38 TJK /08/07 03/08/10 17/05/11 17/05/11 39 TJK /01/98 01/01/98 15/02/11 15/02/11 39 TJK /10/07 22/03/11 22/03/11 22/03/11 40 WGW ND 15/07/05 23/12/08 07/06/06 23/12/08 23/12/08 40 WGW /09/04 19/03/10 24/01/05 24/01/05

2 Table S2: Predicted mir-125b target transcripts encoding enzymes or factors downregulated in MEC2 cells following mir-125b overexpression Gene symbol Gene name Fold down regulati on P value PCTP Phosphatidyl choline transfer protein e-07 TP53INP1 1 Tumor protein p53 inducible nuclear protein e-07 LIPA Lipase A, lysosomal acid, cholesterol Esterase e-07 ACSS1 Acyl-coa synthetase short-chain family member e-07 BIN2 Bridging integrator e-07 SPARC Secreted protein, acidic, cysteine-rich (osteonectin) e-07 TAF4B TAF4b RNA polymerase II, TATA box binding protein e-07 HTATIP2 HIV-1 Tat interactive protein 2, 30kda e-07 FUT7 Fucosyltransferase 7 (alpha (1,3) fucosyltransferase) e-07 FAM102A Family with sequence similarity 102, Member A e-07 DUS1L Dihydrouridine synthase 1-like (S. Cerevisiae) e-07 KLF13 Kruppel-like factor e-07 STARD13 Star-related lipid transfer (START) domain containing e SYTL1 Synaptotagmin-like e-07 KLHL24 Kelch-like e-07 PPP2R1B Protein phosphatase 2 (formerly 2A), regulatory e-07 subunit A, beta isoform CMTM3 CKLF-like MARVEL transmembrane, domain e-07 containing 3 GNPDA1 Glucosamine-6-phosphate deaminase e-06 GPR160 G protein-coupled receptor e-06 IRAK1 Interleukin-1 receptor-associated kinase e-06 TMEM50A Transmembrane protein 50A e-06 GPR109B G protein-coupled receptor 109B e-06 FGFR1 Fibroblast growth factor receptor e-06 VDR 2,3 Vitamin D (1,25- dihydroxy vitamin D3) receptor e-06 NEU1 Sialidase 1 (lysosomal sialidase) e-06 TMEM19 Transmembrane protein e-06 TMEM77 Transmembrane protein e-06 ARHGAP26 Rho gtpase activating protein e-06 RHOQ Ras homolog gene family, member Q e-06 CRTAP Cartilage associated protein e-06 ADPRH ADP-ribosylarginine hydrolase e-06 ATP5G2 ATP synthase, H+ transporting, mitochondrial F e-06 complex, subunit C2 RAB37 RAB37, member RAS oncogene family e-06 LBH Limb bud and heart development homolog e-06 GORASP1 Golgi reassembly stacking protein e-06 ABHD3 Abhydrolase domain containing e-06 NLRC5 NLR family, CARD domain containing e-06 BMF Bcl2 modifying factor e-05 DPH2 DPH2 homolog (S. Cerevisiae) e-05 PPP1R16B Protein phosphatase 1, regulatory subunit 16B e-05 LANCL1 Lanc lantibiotic synthetase component C-like e-05 LIPH Lipase, member H e-05 PAN2 PAN2 polya specific ribonuclease e-05 CCR7 Chemokine (C-C motif) receptor e-05 ABCB9 ATP-binding cassette, sub-family B, member e-05 COL4A3 Collagen, type IV, alpha e-05 ROD1 ROD1 regulator of differentiation e-05 TMEM101 Transmembrane protein e-05

3 ETS1 V-ets erythroblastosis virus E26 oncogene homolog e-05 B3GALTL Beta 1,3 galactosyltransferase-like e-05 ENTPD4 Ectonucleoside triphosphate diphosphohydrolase e-05 DPYSL3 Dihydropyrimidinase-related protein e-05 AGXT2L2 Alanine-glyoxylate aminotransferase 2-like e-05 PDGFD Platelet derived growth factor D e-05 CTDSP2 Carboxy-terminal domain, RNA polymerase II, e-05 polypeptide A, small phosphatase 2 ARID3A AT rich interactive domain 3A e-05 UBE2J1 Ubiquitin-conjugating enzyme E2, J e-05 NAIP NLR family, apoptosis inhibitory protein e-05 PAPLN Papilin e-05 BAZ2A Bromodomain adjacent to zinc finger domain, 2A e-05 RAB3D RAB3D, member RAS oncogene family e-05 SESN2 Sestrin e-05 NLRP1 NLR family, pyrin domain containing e-05 FOXN3 Forkhead box N e-05 MXD4 MAX dimerization protein e-05 TP53 4 Tumor protein p e-05 ZFYVE1 Zinc finger, FYVE domain containing GIMAP6 Gtpase, IMAP family member e-05 ARHGAP25 Rho gtpase activating protein e-05 P2RX4 Purinergic receptor P2X, ligand-gated ion channel, e-05 SNX1 Sorting nexin e-05 FMNL3 Formin-like e-05 NT5DC1 5 nucleotidase domain containing e-05 RNF44 Ring finger protein e-05 ATG4D Autophagy related 4 homolog D, Cysteine protease e-05 ATG4D IER3IP1 Immediate early response 3 interacting protein e-05 STK11IP Serine/threonine kinase 11 interacting protein e-05 MTP18 Mitochondrial protein 18 kda e-05 UNC84A Unc-84 homolog A (C. Elegans) e-05 CORO2A Coronin, actin binding protein, 2A e-05 LACTB Lactamase, beta e-05 HDAC5 Histone deacetylase e-05 MTUS1 Mitochondrial tumor suppressor e-05 PRDM1 3 PR domain containing 1, (BLIMP1) e-05 SLC9A8 Solute carrier family 9 (sodium/hydrogen exchanger) e-05 PCDHGC3 Protocadherin gamma subfamily C, e-05 E2F2 E2F transcription factor e-05 VISA Virus-induced signaling adapter e-05 TRAM2 Translocation associated membrane protein e-05 PSAP Prosaposin, Saposin B (Co-beta-glucosidase) e-05 ZBED1 Zinc finger, BED-type containing e-05 TTC30B Tetratricopeptide repeat domain 30B e-05 LYPLA2 Lysophospholipase II e-05 SEMA4D Sema domain, immunoglobulin domain (Ig), e-05 transmembrane domain (TM) and short cytoplasmic domain, (semaphorin) 4D EMID1 Emilin and multimerin domain-containing protein e-05 TNRC6B Trinucleotide repeat containing 6B e-05 MKNK1 MAP kinase interacting, serine/threonine kinase e-05 SCARB2 Scavenger receptor class B e-05 TAF9B TAF9B RNA polymerase II, TATA box binding e-05 protein (TBP)-associated factor, 31kda DAZAP2 DAZ associated protein e-05 FMR1 Fragile X mental retardation e-05 TUFT1 Tuftelin e-05 ZNF281 Zinc finger protein PPP2R5C Protein phosphatase 2, regulatory subunit gamma ASXL1 Additional sex combs like

4 ERMAP Erythroblast membrane-associated protein SLC38A9 Solute carrier family 38, member PCSK7 Proprotein convertase subtilisin/kexin type RBM38 RNA binding motif protein INSR Insulin receptor TSC22D3 TSC22 domain family, member 3 glucocorticoidinduced leucine zipper (GILZ) TNFSF4 Tumor necrosis factor (ligand) superfamily, member TACSTD2 Tumor-associated calcium signal transducer SEPT6 Septin FLVCR2 Feline leukemia virus subgroup C cellular receptor family, 2 VPS4B Vacuolar protein sorting-associating protein 4B (Suppressor of K(+) transport growth defect 1) EXOC7 Exocyst complex component TBRG1 Transforming growth factor beta regulator NPL N-acetylneuraminate pyruvate lyase KLHL6 Kelch-like 6 (Drosophila) AKAP13 A kinase (PRKA) anchor protein PGPEP1 Pyroglutamyl-peptidase I ANTXR2 Anthrax toxin receptor NAPB N-ethylmaleimide-sensitive factor, attachment protein, beta CDC2L6 Cell division cycle 2-like 6 (CDK8- like) IRF4 5 Interferon regulatory factor SEC31B SEC31 homolog B (S. Cerevisiae) CDC42SE1 CDC42 small effector SYVN1 Synovial apoptosis inhibitor 1, synoviolin VANGL1 Vang-like 1 (van gogh, Drosophila) PSMD9 Proteasome (prosome, macropain) 26S, subunit, nonatpase, BAK1 BCL2-antagonist/killer FNBP1 Formin binding protein ATP8B2 Atpase, class I, type 8B, member METTL9 Methyltransferase like SLC26A6 Solute carrier family 26, member HHAT Hedgehog acyltransferase CLN6 Ceroid-lipofuscinosis, neuronal 6, MAN1B1 Mannosidase, alpha, class 1B, member RABEP2 Rabaptin, RAB gtpase binding effector protein RPL28 Ribosomal protein L LNPEP Leucyl/cystinyl aminopeptidase CYFIP2 Cytoplasmic FMR1 interacting protein AMT Aminomethyltransferase ATP10D Atpase, class V, type 10D SMEK1 SMEK homolog 1, suppressor of mek RAF1 V-raf-1 murine leukemia viral GSS Glutathione synthetase BDH1 3-hydroxybutyrate dehydrogenase, type WWC3 WWC family member FAM134C Family with sequence similarity 134, member C CREB3L2 Camp responsive element binding protein 3-like PSMB9 Proteasome (prosome, macropain) subunit, beta type, (large multifunctional peptidase 2) ZNF10 Zinc finger protein KLHL14 Kelch-like 14 (Drosophila) CCDC21 Coiled-coil domain containing RFX5 Regulatory factor X, ARSD Arylsulfatase D PIK3IP1 Phosphoinositide-3-kinase interacting protein MCL1 Myeloid cell leukemia sequence M6PR Mannose-6-phosphate receptor (cation dependent)

5 CPSF6 Cleavage and polyadenylation specific factor 6, TMEM198 Transmembrane protein SEMA4B Sema domain 4B PDXDC1 Pyridoxal-dependent decarboxylase domain containing IKZF2 IKAROS family zinc finger 2 (Helios) NT5E 5'-nucleotidase, ecto (CD73) MAP3K1 Mitogen-activated protein kinase kinase kinase C9orf86 Chromosome 9 open reading frame ARHGEF2 Rho/rac guanine nucleotide exchange factor (GEF) CARS2 Cysteinyl-trna synthetase 2, mitochondrial BAGE2 B melanoma antigen family, member TAZ Tafazzin ( Lysophospholipid acyltransferases) ZNF697 Zinc finger protein ITCH Itchy E3 ubiquitin protein ligase homolog (mouse) ABTB1 Ankyrin repeat and BTB (POZ) domain containing ERMP1 Endoplasmic reticulum metallopeptidase GOLGB1 Golgin B1, golgi integral membrane protein C11orf24 Chromosome 11 open reading frame THOC6 THO complex 6 homolog TXNDC6 Thioredoxin domain containing 6 ( Protein Disulfide Oxidoreductases) ATP2A3 Atpase, Ca++ transporting, ubiquitous FRAT2 Frequently rearranged in advanced Tcell lymphomas IGF1R Insulin-like growth factor 1 receptor IKZF3 IKAROS family zinc finger 3 (Einos) Validated targets of mir-125: 1. Gururajan, M. et al. MicroRNA-125b inhibition of B cell differentiation in germinal centers. Int. Immunol. 7, (2010). 2. Mohri, T., Nakajima, M., Takagi, S., Komagata, S. & Yokoi, T. MicroRNA regulates human vitamin D receptor. Int. J. Cancer 125, (2009). 3. Zhang, L., Stokes, N., Polak, L. & Fuchs, E. Specific micrornas are preferentially expressed by skin stem cells to balance self-renewal and early lineage commitment. Cell Stem Cell 8, (2011). 4. Le, M.T. et al. MicroRNA-125b is a novel negative regulator of p53. Genes Dev. 3, (2009). 5. Malumbres, R. et al. Differentiation stage-specific expression of micrornas in B lymphocytes and diffuse large B-cell lymphomas. Blood 113, (2009).

6 p-value q-value p-value q-value p-value q-value Table S3: Heat map of statistically significant biochemicals profiled in this study. For paired comparisons, shaded cells indicate p 0.05 (red indicates that the mean values are significantly higher for that comparison; green values significantly lower). Blue-bolded text indicates 0.05< p< All data normalized using Bradford protein concentration. Fold of Change Welch's Two-Sample t-test Statistical Value Welch's Two-Sample t-test Mean Values PATHWAY SORT SUPER PATHWAY SUB PATHWAY BIOCHEMICAL NAME PLATFORM COMP ID KEGG HMDB IND CTRL AGG CTRL AGG IND IND / CTRL AGG / CTRL AGG / IND CTRL IND AGG Super Pathway Sub Pathway PUBCHEM CAS RI MASS 1 glycine GC/MS C00037 HMDB Amino acid Glycine, serine and threonine metabolism ; serine GC/MS 1648 C00065 HMDB Amino acid Glycine, serine and threonine metabolism ; Glycine, serine and threonine metabolism 10 N-acetylserine LC/MS pos HMDB Amino acid Glycine, serine and threonine metabolism ; threonine LC/MS pos 1284 C00188 HMDB Amino acid Glycine, serine and threonine metabolism ; aspartate GC/MS C00049 HMDB Amino acid Alanine and aspartate metabolism ; asparagine GC/MS C00152 HMDB Amino acid Alanine and aspartate metabolism ; Alanine and aspartate metabolism beta-alanine GC/MS 55 C00099 HMDB Amino acid Alanine and aspartate metabolism ; ; alanine GC/MS 1126 C00041 HMDB Amino acid Alanine and aspartate metabolism ; N-acetylalanine LC/MS neg 1585 C02847 HMDB Amino acid Alanine and aspartate metabolism ; glutamate LC/MS pos 57 C00025 HMDB Amino acid Glutamate metabolism ; glutamine LC/MS pos 53 C00064 HMDB Amino acid Glutamate metabolism ; Glutamate metabolism 45 pyroglutamine* LC/MS pos Amino acid Glutamate metabolism gamma-aminobutyrate (GABA) GC/MS 1416 C00334 HMDB Amino acid Glutamate metabolism ; Histidine metabolism histidine LC/MS neg 59 C00135 HMDB Amino acid Histidine metabolism ; lysine GC/MS 1301 C00047 HMDB Amino acid Lysine metabolism ; Lysine metabolism 2-aminoadipate GC/MS 6146 C00956 HMDB Amino acid Lysine metabolism ; ; N6-acetyllysine LC/MS pos C02727 HMDB < < Amino acid Lysine metabolism ; phenylalanine LC/MS pos 64 C00079 HMDB Amino acid Phenylalanine & tyrosine metabolism ; p-cresol sulfate LC/MS neg C Amino acid Phenylalanine & tyrosine metabolism ; Phenylalanine & tyrosine metabolism tyrosine LC/MS pos 1299 C00082 HMDB Amino acid Phenylalanine & tyrosine metabolism ; (4-hydroxyphenyl)lactate LC/MS neg C03672 HMDB Amino acid Phenylalanine & tyrosine metabolism ; phenylacetylglycine LC/MS neg C05598 HMDB Amino acid Phenylalanine & tyrosine metabolism ; kynurenine LC/MS pos C00328 HMDB Amino acid Tryptophan metabolism ; tryptophan LC/MS pos 54 C00078 HMDB Amino acid Tryptophan metabolism ; Tryptophan metabolism tryptophan betaine LC/MS pos C Amino acid Tryptophan metabolism ; serotonin (5HT) LC/MS pos 2342 C00780 HMDB Amino acid Tryptophan metabolism ; C-glycosyltryptophan* LC/MS pos Amino acid Tryptophan metabolism methyl-2-oxovalerate LC/MS neg C00671 HMDB Amino acid Valine, leucine and isoleucine metabolism ; beta-hydroxyisovalerate LC/MS neg HMDB < < Amino acid Valine, leucine and isoleucine metabolism ; isoleucine LC/MS pos 1125 C00407 HMDB Amino acid Valine, leucine and isoleucine metabolism ; leucine LC/MS pos 60 C00123 HMDB Amino acid Valine, leucine and isoleucine metabolism ; valine LC/MS pos 1649 C00183 HMDB Amino acid Valine, leucine and isoleucine metabolism ; Valine, leucine and isoleucine metabolism methyl-2-oxopentanoate LC/MS neg C00233 HMDB Amino acid Valine, leucine and isoleucine metabolism ; isobutyrylcarnitine LC/MS pos < < Amino acid Valine, leucine and isoleucine metabolism ; Amino acid 2-methylbutyroylcarnitine LC/MS pos HMDB < < Amino acid Valine, leucine and isoleucine metabolism ; isovalerylcarnitine LC/MS pos HMDB < < Amino acid Valine, leucine and isoleucine metabolism hydroxyisovaleroyl carnitine LC/MS pos Amino acid Valine, leucine and isoleucine metabolism ; cysteine GC/MS C00097 HMDB < < Amino acid Cysteine, methionine, SAM, taurine metabolism ; ; S-methylcysteine GC/MS HMDB Amino acid Cysteine, methionine, SAM, taurine metabolism ; methionine sulfoxide LC/MS pos C02989 HMDB Amino acid Cysteine, methionine, SAM, taurine metabolism ; hypotaurine GC/MS 590 C00519 HMDB Amino acid Cysteine, methionine, SAM, taurine metabolism ; Cysteine, methionine, SAM, taurine metabolism taurine GC/MS 2125 C00245 HMDB Amino acid Cysteine, methionine, SAM, taurine metabolism ; S-adenosylhomocysteine (SAH) LC/MS pos C00021 HMDB < < Amino acid Cysteine, methionine, SAM, taurine metabolism ; methionine LC/MS pos 1302 C00073 HMDB Amino acid Cysteine, methionine, SAM, taurine metabolism ; N-acetylmethionine LC/MS neg 1589 C02712 HMDB Amino acid Cysteine, methionine, SAM, taurine metabolism ; hydroxybutyrate (AHB) GC/MS C05984 HMDB Amino acid Cysteine, methionine, SAM, taurine metabolism ; HMDB01539,H 240 dimethylarginine (SDMA + ADMA) LC/MS pos C Amino acid Urea cycle; arginine-, proline-, metabolism MDB arginine LC/MS neg 1638 C00062 HMDB Amino acid Urea cycle; arginine-, proline-, metabolism ; ornithine GC/MS 1493 C00077 HMDB Amino acid Urea cycle; arginine-, proline-, metabolism ; urea GC/MS 1670 C00086 HMDB Amino acid Urea cycle; arginine-, proline-, metabolism ; Urea cycle; arginine-, proline-, metabolism proline LC/MS pos 1898 C00148 HMDB Amino acid Urea cycle; arginine-, proline-, metabolism ; citrulline LC/MS pos 2132 C00327 HMDB < < Amino acid Urea cycle; arginine-, proline-, metabolism ; N-acetylornithine LC/MS pos C00437 HMDB Amino acid Urea cycle; arginine-, proline-, metabolism ; trans-4-hydroxyproline GC/MS 1366 C01157 HMDB Amino acid Urea cycle; arginine-, proline-, metabolism ; argininosuccinate GC/MS C03406 HMDB Amino acid Urea cycle; arginine-, proline-, metabolism ; creatine LC/MS pos C00300 HMDB < < Amino acid Creatine metabolism ; Creatine metabolism 260 creatinine LC/MS pos 513 C00791 HMDB Amino acid Creatine metabolism ; Butanoate metabolism 2-aminobutyrate GC/MS 1577 C02261 HMDB Amino acid Butanoate metabolism ; methylthioadenosine (MTA) LC/MS pos 1419 C00170 HMDB < < Amino acid Polyamine metabolism ; Polyamine metabolism spermidine LC/MS pos 485 C00315 HMDB < < Amino acid Polyamine metabolism ; spermine LC/MS pos 603 C00750 HMDB < < Amino acid Polyamine metabolism ; guanidinobutanoate LC/MS pos C01035 HMDB Amino acid Guanidino and acetamido metabolism ; ; Guanidino and acetamido metabolism acetamidobutanoate LC/MS pos 1558 C02946 HMDB < Amino acid Guanidino and acetamido metabolism ; glutathione, reduced (GSH) LC/MS pos 2127 C00051 HMDB < < Amino acid Glutathione metabolism ; oxoproline LC/MS neg 1494 C01879 HMDB Amino acid Glutathione metabolism ; glutathione, oxidized (GSSG) LC/MS pos C00127 HMDB < < Amino acid Glutathione metabolism ; Glutathione metabolism 284 cysteine-glutathione disulfide LC/MS pos HMDB Amino acid Glutathione metabolism ; ophthalmate LC/MS pos HMDB < < Amino acid Glutathione metabolism ; S-lactoylglutathione LC/MS neg C03451 HMDB < < Amino acid Glutathione metabolism ; glycylglycine GC/MS C02037 HMDB Peptide Dipeptide ; glycylleucine LC/MS pos C02155 HMDB < Peptide Dipeptide ; alanylalanine GC/MS C00993 HMDB Peptide Dipeptide ; alanylleucine LC/MS pos < < Peptide Dipeptide alanylglutamate LC/MS pos < Peptide Dipeptide alpha-glutamylglutamate LC/MS pos C Peptide Dipeptide ; isoleucylleucine LC/MS pos Peptide Dipeptide ; pro-hydroxy-pro LC/MS pos HMDB Peptide Dipeptide ; pyroglutamylglycine LC/MS neg Peptide Dipeptide pyroglutamylglutamine LC/MS neg Peptide Dipeptide ; pyroglutamylvaline LC/MS pos Peptide Dipeptide valylglutamate LC/MS pos Peptide Dipeptide ; cyclo(phe-pro) LC/MS pos Peptide Dipeptide cyclo(leu-phe) LC/MS pos Peptide Dipeptide cyclo(leu-ala) GC/MS Peptide Dipeptide ; Dipeptide cyclo(leu-pro) LC/MS pos Peptide Dipeptide cyclo(glu-glu) LC/MS pos Peptide Dipeptide cyclo(gly-phe) GC/MS Peptide Dipeptide Peptide 356 valylleucine LC/MS pos < Peptide Dipeptide cyclo(phe-phe) LC/MS pos Peptide Dipeptide ; aspartylleucine LC/MS pos < Peptide Dipeptide ; isoleucylglycine LC/MS pos Peptide Dipeptide ; isoleucylserine LC/MS pos Peptide Dipeptide ; leucylalanine LC/MS pos < Peptide Dipeptide ; leucylglutamate LC/MS pos Peptide Dipeptide leucylglycine LC/MS pos Peptide Dipeptide ; phenylalanylserine LC/MS pos Peptide Dipeptide ; serylleucine LC/MS pos Peptide Dipeptide ; threonylleucine LC/MS pos < Peptide Dipeptide ; tyrosylleucine LC/MS pos Peptide Dipeptide ; valylisoleucine LC/MS pos Peptide Dipeptide ; Dipeptide derivative carnosine LC/MS neg 1768 C00386 HMDB Peptide Dipeptide derivative ; gamma-glutamylleucine LC/MS pos HMDB Peptide gamma-glutamyl ; gamma-glutamylisoleucine* LC/MS pos HMDB Peptide gamma-glutamyl gamma-glutamyl 412 gamma-glutamylphenylalanine LC/MS pos HMDB Peptide gamma-glutamyl ; gamma-glutamyltyrosine LC/MS pos Peptide gamma-glutamyl ; erythronate* GC/MS HMDB Carbohydrate Aminosugars metabolism ; Aminosugars metabolism 455 N-acetylneuraminate GC/MS 1592 C00270 HMDB Carbohydrate Aminosugars metabolism ; fructose GC/MS C00095 HMDB Carbohydrate Fructose, mannose, galactose, starch, and sucrose metabolism ; '-sialyllactose GC/MS G00265 HMDB Carbohydrate Fructose, mannose, galactose, starch, and sucrose metabolism ; maltose GC/MS C00208 HMDB Carbohydrate Fructose, mannose, galactose, starch, and sucrose metabolism ; mannitol GC/MS C00392 HMDB Carbohydrate Fructose, mannose, galactose, starch, and sucrose metabolism ; Fructose, mannose, galactose, starch, and sucrose metabolism mannose-6-phosphate GC/MS 1470 C00275 HMDB Carbohydrate Fructose, mannose, galactose, starch, and sucrose metabolism ; ; stachyose LC/MS neg C01613 HMDB Carbohydrate Fructose, mannose, galactose, starch, and sucrose metabolism ; sorbitol GC/MS C00794 HMDB Carbohydrate Fructose, mannose, galactose, starch, and sucrose metabolism ; sucrose LC/MS neg 1519 C00089 HMDB Carbohydrate Fructose, mannose, galactose, starch, and sucrose metabolism ; raffinose LC/MS neg 586 C00492 HMDB Carbohydrate Fructose, mannose, galactose, starch, and sucrose metabolism ; glycerate GC/MS 1572 C00258 HMDB Carbohydrate Glycolysis, gluconeogenesis, pyruvate metabolism ; Carbohydrate 519 glucose-6-phosphate (G6P) GC/MS C00668 HMDB Carbohydrate Glycolysis, gluconeogenesis, pyruvate metabolism ; glucose GC/MS C00293 HMDB Carbohydrate Glycolysis, gluconeogenesis, pyruvate metabolism ; Glycolysis, gluconeogenesis, pyruvate metabolism phosphoglycerate GC/MS C00631 HMDB < < Carbohydrate Glycolysis, gluconeogenesis, pyruvate metabolism ; phosphoglycerate GC/MS 1414 C00597 HMDB < < Carbohydrate Glycolysis, gluconeogenesis, pyruvate metabolism ; lactate GC/MS 527 C00186 HMDB < Carbohydrate Glycolysis, gluconeogenesis, pyruvate metabolism ; phosphogluconate LC/MS neg C00345 HMDB < < Carbohydrate Nucleotide sugars, pentose metabolism ; ; arabitol GC/MS C00474 HMDB Carbohydrate Nucleotide sugars, pentose metabolism ; ribitol GC/MS C00474 HMDB Carbohydrate Nucleotide sugars, pentose metabolism ; Nucleotide sugars, pentose metabolism threitol GC/MS C16884 HMDB Carbohydrate Nucleotide sugars, pentose metabolism ; ribose GC/MS C00121 HMDB Carbohydrate Nucleotide sugars, pentose metabolism ; Isobar: ribulose 5-phosphate, xylulose 5-phosphate GC/MS Carbohydrate Nucleotide sugars, pentose metabolism xylitol GC/MS 4966 C00379 HMDB Carbohydrate Nucleotide sugars, pentose metabolism ; citrate GC/MS 1564 C00158 HMDB Energy Krebs cycle ; succinate GC/MS 1437 C00042 HMDB < < Energy Krebs cycle ; Krebs cycle 594 fumarate GC/MS 1643 C00122 HMDB < < Energy Krebs cycle ; Energy malate GC/MS 1303 C00149 HMDB < < Energy Krebs cycle ; acetylphosphate GC/MS C00227 HMDB Energy Oxidative phosphorylation ; Oxidative phosphorylation

7 602 phosphate GC/MS C00009 HMDB < Energy Oxidative phosphorylation ; Energy Oxidative phosphorylation 603 pyrophosphate (PPi) GC/MS 2078 C00013 HMDB Energy Oxidative phosphorylation ; linoleate (18:2n6) LC/MS neg 1105 C01595 HMDB < < Lipid Essential fatty acid ; linolenate [alpha or gamma; (18:3n3 or 6)] LC/MS neg C06427 HMDB < < Lipid Essential fatty acid dihomo-linolenate (20:3n3 or n6) LC/MS neg C03242 HMDB < < Lipid Essential fatty acid Essential fatty acid 611 docosapentaenoate (n3 DPA; 22:5n3) LC/MS neg C16513 HMDB Lipid Essential fatty acid ; docosapentaenoate (n6 DPA; 22:5n6) LC/MS neg C06429 HMDB Lipid Essential fatty acid ; docosahexaenoate (DHA; 22:6n3) LC/MS neg C06429 HMDB Lipid Essential fatty acid ; caproate (6:0) LC/MS neg C01585 HMDB < < Lipid Medium chain fatty acid ; caprylate (8:0) LC/MS neg C06423 HMDB Lipid Medium chain fatty acid ; Medium chain fatty acid pelargonate (9:0) LC/MS neg C01601 HMDB < < Lipid Medium chain fatty acid ; caprate (10:0) LC/MS neg 1642 C01571 HMDB Lipid Medium chain fatty acid ; laurate (12:0) LC/MS neg 1645 C02679 HMDB < Lipid Medium chain fatty acid ; myristoleate (14:1n5) LC/MS neg C08322 HMDB < < Lipid Long chain fatty acid ; pentadecanoate (15:0) LC/MS neg 1361 C16537 HMDB < Lipid Long chain fatty acid ; palmitate (16:0) LC/MS neg 1336 C00249 HMDB < Lipid Long chain fatty acid ; palmitoleate (16:1n7) LC/MS neg C08362 HMDB < Lipid Long chain fatty acid ; margarate (17:0) LC/MS neg 1121 HMDB < Lipid Long chain fatty acid ; heptadecenoate (17:1n7) LC/MS neg < Lipid Long chain fatty acid ; stearate (18:0) LC/MS neg 1358 C01530 HMDB < Lipid Long chain fatty acid ; oleate (18:1n9) GC/MS 1359 C00712 HMDB < < Lipid Long chain fatty acid ; Long chain fatty acid cis-vaccenate (18:1n7) GC/MS C < Lipid Long chain fatty acid ; nonadecanoate (19:0) LC/MS neg 1356 C16535 HMDB Lipid Long chain fatty acid ; nonadecenoate (19:1n9) LC/MS neg < < Lipid Long chain fatty acid ; eicosenoate (20:1n9 or 11) LC/MS neg HMDB < < Lipid Long chain fatty acid dihomo-linoleate (20:2n6) LC/MS neg C < < Lipid Long chain fatty acid ; mead acid (20:3n9) LC/MS neg HMDB Lipid Long chain fatty acid ; arachidonate (20:4n6) LC/MS neg 1110 C00219 HMDB Lipid Long chain fatty acid ; docosadienoate (22:2n6) LC/MS neg C Lipid Long chain fatty acid ; adrenate (22:4n6) LC/MS neg C16527 HMDB Lipid Long chain fatty acid ; hydroxystearate LC/MS neg C Lipid Fatty acid, monohydroxy ; Fatty acid, monohydroxy hydroxypalmitate LC/MS neg Lipid Fatty acid, monohydroxy ; Fatty acid, dicarboxylate 2-hydroxyglutarate GC/MS C02630 HMDB < Lipid Fatty acid, dicarboxylate ; Fatty acid, amide stearamide GC/MS C Lipid Fatty acid, amide ; Fatty acid, branched 17-methylstearate LC/MS neg Lipid Fatty acid, branched ; Eicosanoid 12-HETE LC/MS neg HMDB < < Lipid Eicosanoid ; Endocannabinoid oleic ethanolamide LC/MS neg HMBD < < Lipid Endocannabinoid ; ; propionylcarnitine LC/MS pos C03017 HMDB < < Lipid Fatty acid metabolism (also BCAA metabolism) ; Fatty acid metabolism (also BCAA metabolism) 811 butyrylcarnitine LC/MS pos < Lipid Fatty acid metabolism (also BCAA metabolism) ; deoxycarnitine LC/MS pos C01181 HMDB < < Lipid Carnitine metabolism ; carnitine LC/MS pos < < Lipid Carnitine metabolism ; dehydrocarnitine* LC/MS pos C02636 HMDB < < Lipid Carnitine metabolism ; Carnitine metabolism 822 acetylcarnitine LC/MS pos C02571 HMDB Lipid Carnitine metabolism ; palmitoylcarnitine LC/MS pos Lipid Carnitine metabolism ; oleoylcarnitine LC/MS pos HMDB Lipid Carnitine metabolism cholate LC/MS neg C00695 HMDB Lipid Bile acid metabolism ; glycocholate LC/MS neg C01921 HMDB Lipid Bile acid metabolism ; ; Lipid Bile acid metabolism taurocholate LC/MS neg C05122 HMDB Lipid Bile acid metabolism ; taurochenodeoxycholate LC/MS neg C05465 HMDB Lipid Bile acid metabolism ; glycochenodeoxycholate LC/MS neg C05466 HMDB Lipid Bile acid metabolism ; choline phosphate LC/MS pos < < Lipid Glycerolipid metabolism ; ethanolamine GC/MS 1497 C00189 HMDB Lipid Glycerolipid metabolism ; phosphoethanolamine GC/MS C00346 HMDB Lipid Glycerolipid metabolism ; Glycerolipid metabolism glycerol GC/MS C00116 HMDB Lipid Glycerolipid metabolism ; choline LC/MS pos < < Lipid Glycerolipid metabolism ; glycerol 3-phosphate (G3P) GC/MS C00093 HMDB < Lipid Glycerolipid metabolism ; glycerophosphorylcholine (GPC) LC/MS pos C00670 HMDB < Lipid Glycerolipid metabolism ; myo-inositol GC/MS C00137 HMDB Lipid Inositol metabolism ; chiro-inositol GC/MS Lipid Inositol metabolism ; pinitol GC/MS C Lipid Inositol metabolism ; Inositol metabolism 893 inositol 1-phosphate (I1P) GC/MS 1481 HMDB < Lipid Inositol metabolism ; scyllo-inositol GC/MS C06153 HMDB Lipid Inositol metabolism ; myo-inositol pentakisphosphate (1,2,4,5,6 or 902 LC/MS neg < Lipid Inositol metabolism ,3,4,5,6) palmitoylglycerophosphoethanolamine LC/MS neg HMDB Lipid Lysolipid stearoylglycerophosphoethanolamine LC/MS neg HMDB Lipid Lysolipid ; oleoylglycerophosphoethanolamine LC/MS neg HMDB < < Lipid Lysolipid oleoylglycerophosphoethanolamine* LC/MS neg < Lipid Lysolipid linoleoylglycerophosphoethanolamine* LC/MS neg HMDB < Lipid Lysolipid linoleoylglycerophosphoethanolamine* LC/MS pos Lipid Lysolipid arachidonoylglycerophosphoethanolamine* LC/MS neg HMDB < < Lipid Lysolipid arachidonoylglycerophosphoethanolamine* LC/MS pos Lipid Lysolipid docosapentaenoylglycerophosphoethanolamine* LC/MS pos Lipid Lysolipid docosahexaenoylglycerophosphoethanolamine* LC/MS pos Lipid Lysolipid Lysolipid palmitoylglycerophosphocholine LC/MS pos Lipid Lysolipid ; palmitoylglycerophosphocholine* LC/MS pos Lipid Lysolipid stearoylglycerophosphocholine LC/MS pos Lipid Lysolipid ; oleoylglycerophosphocholine LC/MS pos Lipid Lysolipid ; oleoylglycerophosphocholine* LC/MS pos Lipid Lysolipid arachidonoylglycerophosphocholine* LC/MS pos Lipid Lysolipid stearoylglycerophosphoinositol LC/MS neg < Lipid Lysolipid arachidonoylglycerophosphoinositol* LC/MS neg < < Lipid Lysolipid oleoylglycerophosphoserine LC/MS neg Lipid Lysolipid palmitoylplasmenylethanolamine* LC/MS neg Lipid Lysolipid palmitoylglycerol (1-monopalmitin) GC/MS < < Lipid Monoacylglycerol ; Monoacylglycerol stearoylglycerol (1-monostearin) GC/MS D Lipid Monoacylglycerol ; Neurotransmitter acetylcholine LC/MS pos C01996 HMDB Lipid Neurotransmitter ; sphingosine LC/MS pos C00319 HMDB Lipid Sphingolipid ; Sphingolipid palmitoyl sphingomyelin GC/MS < < Lipid Sphingolipid stearoyl sphingomyelin GC/MS C00550 HMDB Lipid Sphingolipid ; ; lathosterol GC/MS C01189 HMDB Lipid Sterol/Steroid ; cholesterol GC/MS 63 C00187 HMDB Lipid Sterol/Steroid ; Sterol/Steroid alpha-hydroxycholesterol GC/MS C03594 HMDB Lipid Sterol/Steroid ; beta-hydroxycholesterol GC/MS C03594 HMDB Lipid Sterol/Steroid ; xanthine GC/MS 3147 C00385 HMDB Nucleotide Purine metabolism, (hypo)xanthine/inosine containing ; hypoxanthine LC/MS neg 3127 C00262 HMDB Nucleotide Purine metabolism, (hypo)xanthine/inosine containing ; Purine metabolism, (hypo)xanthine/inosine containing 1099 inosine LC/MS neg Nucleotide Purine metabolism, (hypo)xanthine/inosine containing ; inosine 5'-monophosphate (IMP) LC/MS pos 2133 C00130 HMDB Nucleotide Purine metabolism, (hypo)xanthine/inosine containing ; adenine GC/MS 554 C00147 HMDB < < Nucleotide Purine metabolism, adenine containing ; adenosine LC/MS pos 555 C00212 HMDB < < Nucleotide Purine metabolism, adenine containing ; adenosine 2'-monophosphate (2'-AMP) LC/MS pos C00946 HMDB Nucleotide Purine metabolism, adenine containing ; Purine metabolism, adenine containing 1113 adenosine 3'-monophosphate (3'-AMP) LC/MS pos C01367 HMDB < < Nucleotide Purine metabolism, adenine containing ; adenosine 5'-monophosphate (AMP) LC/MS pos C00020 HMDB < Nucleotide Purine metabolism, adenine containing ; adenosine 5'-diphosphate (ADP) LC/MS neg 3108 C00008 HMDB Nucleotide Purine metabolism, adenine containing ; guanine LC/MS pos C00242 HMDB Nucleotide Purine metabolism, guanine containing ; Nucleotide 1128 Purine metabolism, guanine containing guanosine LC/MS pos 1573 C00387 HMDB Nucleotide Purine metabolism, guanine containing ; guanosine 5'- monophosphate (5'-GMP) LC/MS pos < Nucleotide Purine metabolism, guanine containing ; urate GC/MS 1604 C00366 HMDB Nucleotide Purine metabolism, urate metabolism ;120K5305; Purine metabolism, urate metabolism 1150 allantoin GC/MS 1107 C02350 HMDB Nucleotide Purine metabolism, urate metabolism ; Pyrimidine metabolism, cytidine containing cytosine-2',3'-cyclic monophosphate LC/MS neg C02354 HMDB < < Nucleotide Pyrimidine metabolism, cytidine containing ; uracil GC/MS 605 C00106 HMDB < < Nucleotide Pyrimidine metabolism, uracil containing ; uridine LC/MS neg 606 C00299 HMDB < < Nucleotide Pyrimidine metabolism, uracil containing ; Pyrimidine metabolism, uracil containing pseudouridine LC/MS pos C02067 HMDB < Nucleotide Pyrimidine metabolism, uracil containing ; uridine monophosphate (5' or 3') LC/MS pos < < Nucleotide Pyrimidine metabolism, uracil containing uridine-2',3'-cyclic monophosphate LC/MS neg C02355 HMDB < < Nucleotide Pyrimidine metabolism, uracil containing Purine and pyrimidine metabolism methylphosphate GC/MS Nucleotide Purine and pyrimidine metabolism ; ascorbate (Vitamin C) GC/MS 1640 C00072 HMDB < < Cofactors and vitamins Ascorbate and aldarate metabolism ; threonate GC/MS C01620 HMDB < < Cofactors and vitamins Ascorbate and aldarate metabolism ; Ascorbate and aldarate metabolism 1200 glucarate (saccharate) GC/MS 1476 C00818 HMDB Cofactors and vitamins Ascorbate and aldarate metabolism ; arabonate GC/MS HMDB Cofactors and vitamins Ascorbate and aldarate metabolism ; nicotinamide LC/MS pos 594 C00153 HMDB < < Cofactors and vitamins Nicotinate and nicotinamide metabolism ; Cofactors and vitamins Nicotinate and nicotinamide metabolism nicotinamide adenine dinucleotide (NAD+) LC/MS pos 5278 C00003 HMDB < < Cofactors and vitamins Nicotinate and nicotinamide metabolism ###################### ; trigonelline (N'-methylnicotinate) LC/MS pos HMDB Cofactors and vitamins Nicotinate and nicotinamide metabolism ; Pantothenate and CoA metabolism pantothenate LC/MS pos 1508 C00864 HMDB Cofactors and vitamins Pantothenate and CoA metabolism ; Riboflavin metabolism flavin adenine dinucleotide (FAD) LC/MS neg 2134 C00016 HMDB Cofactors and vitamins Riboflavin metabolism ; ; Tocopherol metabolism alpha-tocopherol GC/MS 1561 C02477 HMDB < < Cofactors and vitamins Tocopherol metabolism ; ; Vitamin B6 metabolism pyridoxate LC/MS neg C00847 HMDB Cofactors and vitamins Vitamin B6 metabolism ; hippurate LC/MS neg C01586 HMDB Xenobiotics Benzoate metabolism ; Benzoate metabolism 3-hydroxyhippurate LC/MS neg HMDB Xenobiotics Benzoate metabolism catechol sulfate LC/MS neg C < < Xenobiotics Benzoate metabolism glycolate (hydroxyacetate) GC/MS C00160 HMDB Xenobiotics Chemical ; phenoxyethanol GC/MS Xenobiotics Chemical ; Chemical 1375 ectoine LC/MS pos C Xenobiotics Chemical ; Xenobiotics phenol red LC/MS neg C Xenobiotics Chemical ; daidzein LC/MS neg C10208 HMDB Xenobiotics Food component/plant ; genistein LC/MS neg C06563 HMDB Xenobiotics Food component/plant ; Food component/plant ergothioneine LC/MS pos C05570 HMDB < Xenobiotics Food component/plant ; stachydrine LC/MS pos C10172 HMDB Xenobiotics Food component/plant ; homostachydrine* LC/MS pos C Xenobiotics Food component/plant ; Sugar, sugar substitute, starch erythritol GC/MS C00503 HMDB Xenobiotics Sugar, sugar substitute, starch ;

8 Table S4: Genes encoding the human aldehyde dehydrogenases are mostly located in CLL-susceptible loci Gene Name and Function Location Ref. ALDH1A1 aldehyde dehydrogenase 1 family, member A1 9q21.13 retinol metabolism; regulation of the metabolic responses to high-fat diet ALDH1A2 aldehyde dehydrogenase 1 family, member A2 15q catalyzes the synthesis of retinoic acid from retinaldehyde ALDH1A3 aldehyde dehydrogenase 1 family, member A3 15q26.3 uses retinal as a substrate ALDH1B1 aldehyde dehydrogenase 1 family, member B1 9p11.1 unknown ALDH1L1 aldehyde dehydrogenase 1 family, member L1 3q converts 10-formyltetrahydrofolate, NADP, and water to tetrahydrofolate, NADPH, and carbon dioxide ALDH1L2 aldehyde dehydrogenase 1 family, member L2 12q converts 10-formyltetrahydrofolate to tetrahydrofolate and CO2 in an NADP(+)-dependent reaction ALDH2 aldehyde dehydrogenase 2 family 12q alcohol metabolism ALDH3A1 aldehyde dehydrogenase 3 family, member A1 17p oxidizes aromatic and medium-chain saturated and unsaturated aldehyde substrates ALDH3A2 aldehyde dehydrogenase 3 family, member A2 17p catalyzes the oxidation of long-chain aliphatic aldehydes to fatty acid ALDH3B1 aldehyde dehydrogenase 3 family, member B1 11q13 6 unknown ALDH3B2 aldehyde dehydrogenase 3 family, member B2 11q13 6 unknown ALDH4A1 aldehyde dehydrogenase 4 family, member A1 1p36 7 proline degradation; converts pyrroline-5-carboxylate to glutamate ALDH5A1 aldehyde dehydrogenase 5 family, member A1 6p22 8 mitochondrial NAD(+)-dependent succinic semialdehyde dehydrogenase ALDH6A1 aldehyde dehydrogenase 6 family, member A1 14q catalyzes the irreversible oxidative decarboxylation of malonate and methylmalonate semialdehydes to acetyl- and propionyl-coa ALDH7A1 aldehyde dehydrogenase 7 family, member A1 5q31 protects against hyperosmotic stress presumably through the generation of betaine, an important cellular osmolyte, formed from betaine aldehyde. Hyperosmotic stress is coupled to an increase in oxidative stress and lipid peroxidation (LPO) ALDH8A1 aldehyde dehydrogenase 8 family, member A1 6q

9 converts 9-cis-retinal into the retinoid X receptor ligand 9-cisretinoic acid ALDH9A1 aldehyde dehydrogenase 9 family, member A1 1q catalyzes the dehydrogenation of gamma-aminobutyraldehyde to gamma-aminobutyric acid ALDH16A aldehyde dehydrogenase 16 family, member A1 19q act on aldehyde substrates and use nicotinamide adenine dinucleotide phosphate (NADP) as a cofactor ALDH18A aldehyde dehydrogenase 18 family, member A1 10q catalyzes the reduction of glutamate to delta1-pyrroline-5- carboxylate, a critical step in the de novo biosynthesis of proline, ornithine and arginine 74% of ALDHs are located in CLL-susceptible loci (shown in bold and underlined) 1. Crowther-Swanepoel, D et al. Common variants at 2q37.3, 8q24.21, 15q21.3 and 16q24.1 influence chronic lymphocytic leukemia risk. Nat. Genet. 42, (2010). 2. Yağci, M., Sucak, G.T., Oğur, G. & Haznedar, R. Therapy-related refractory anemia with ringed sideroblasts in chronic lymphocytic leukemia. Involvement of 3q21 region. Cancer Genet. Cytogenet. 129, (2001). 3. Schmidt, H.H. et al. Deregulation of the carbohydrate (chondroitin 4) sulfotransferase 11 (CHST11) gene in a B-cell chronic lymphocytic leukemia with a t(12;14)(q23;q32). Oncogene 23, (2004). 4. Ng, D. et al. High-density mapping and follow-up studies on chromosomal regions 1, 3, 6, 12, 13 and 17 in 28 families with chronic lymphocytic leukaemia. Br. J. Haematol. 133, (2006). 5. Fink, S.R. et al. Loss of TP53 is due to rearrangements involving chromosome region 17p10 approximately p12 in chronic lymphocytic leukemia. Cancer Genet. Cytogenet. 167, (2006). 6. Koduru, P.R., Offit, K. & Filippa, D.A. Molecular analysis of breaks in BCL-1 protooncogene in B-cell lymphomas with abnormalities of 11q13. Oncogene 4, (1989). 7. Leupin, N. et al. P73 status in B-cell chronic lymphocytic leukaemia. Leuk. Lymphoma 45, (2004). 8. Sellick, G.S et al. A high-density SNP genomewide linkage scan for chronic lymphocytic leukemia-susceptibility loci. Am. J. Hum. Genet. 77, (2005). 9. Autio, K. et al. Low number of DNA copy number changes in small lymphocytic lymphoma. Haematologica 83, (1998). 10. Amiel, A. et al. Deletion of 6q27 in chronic lymphocytic leukemia and multiple myeloma detected by fluorescence in situ hybridization. Cancer Genet. Cytogenet. 112, (1999). 11. Tyybakinoja, A., Vilpo, J. & Knuutila, S. High-resolution oligonucleotide array-cgh pinpoints genes involved in cryptic losses in chronic lymphocytic leukemia. Cytogenet. Genome Res. 118, 8-12 (2007). 12. Crowther-Swanepoel, D. et al. Verification that common variation at 2q37.1, 6p25.3, 11q24.1, 15q23, and 19q13.32 influences chronic lymphocytic leukaemia risk. Br. J. Haematol. 150, (2010).

10 p-value q-value p-value q-value p-value q-value 1 glycine GC/MS C00037 HMDB Amino acid Glycine, serine and threonine metabolism ; N-acetylglycine GC/MS HMDB Amino acid Glycine, serine and threonine metabolism ; serine GC/MS 1648 C00065 HMDB Amino acid Glycine, serine and threonine metabolism ; N-acetylserine LC/MS pos HMDB Amino acid Glycine, serine and threonine metabolism ; homoserine GC/MS C00263,C HMDB Amino acid Glycine, serine and threonine metabolism ; threonine LC/MS pos 1284 C00188 HMDB Amino acid Glycine, serine and threonine metabolism ; N-acetylthreonine LC/MS neg C Amino acid Glycine, serine and threonine metabolism betaine LC/MS pos 3141 HMDB Amino acid Glycine, serine and threonine metabolism ; aspartate GC/MS C00049 HMDB Amino acid Alanine and aspartate metabolism ; asparagine LC/MS pos 512 C00152 HMDB < Amino acid Alanine and aspartate metabolism ; beta-alanine GC/MS 55 C00099 HMDB Amino acid Alanine and aspartate metabolism ; ; alanine GC/MS 1126 C00041 HMDB Amino acid Alanine and aspartate metabolism ; N-acetylalanine LC/MS neg 1585 C02847 HMDB Amino acid Alanine and aspartate metabolism ; N-carbamoylaspartate GC/MS 1594 C00438 HMDB Amino acid Alanine and aspartate metabolism ; N-acetylaspartate (NAA) LC/MS pos C01042 HMDB Amino acid Alanine and aspartate metabolism ; ; glutamate LC/MS pos 57 C00025 HMDB Amino acid Glutamate metabolism ; glutamate, gamma-methyl ester LC/MS pos Amino acid Glutamate metabolism ; glutamine LC/MS pos 53 C00064 HMDB Amino acid Glutamate metabolism ; pyroglutamine* LC/MS pos Amino acid Glutamate metabolism gamma-aminobutyrate (GABA) GC/MS 1416 C00334 HMDB Amino acid Glutamate metabolism ; N-acetyl-aspartyl-glutamate (NAAG) LC/MS pos C12270 HMDB Amino acid Glutamate metabolism ; histidine LC/MS neg 59 C00135 HMDB Amino acid Histidine metabolism ; trans-urocanate LC/MS pos 607 C00785 HMDB Amino acid Histidine metabolism ; glutarate (pentanedioate) GC/MS 396 C00489 HMDB Amino acid Lysine metabolism ; lysine GC/MS 1301 C00047 HMDB Amino acid Lysine metabolism ; aminoadipate GC/MS 6146 C00956 HMDB Amino acid Lysine metabolism ; ; N6-acetyllysine LC/MS pos C02727 HMDB Amino acid Lysine metabolism ; phenylalanine LC/MS pos 64 C00079 HMDB Amino acid Phenylalanine & tyrosine metabolism ; p-cresol sulfate LC/MS neg C Amino acid Phenylalanine & tyrosine metabolism ; tyrosine LC/MS pos 1299 C00082 HMDB Amino acid Phenylalanine & tyrosine metabolism ; (4-hydroxyphenyl)lactate LC/MS neg C03672 HMDB Amino acid Phenylalanine & tyrosine metabolism ; tyramine LC/MS pos 1603 C00483 HMDB Amino acid Phenylalanine & tyrosine metabolism ; phenylacetylglycine LC/MS neg C05598 HMDB Amino acid Phenylalanine & tyrosine metabolism ; kynurenine LC/MS pos C00328 HMDB Amino acid Tryptophan metabolism ; tryptophan LC/MS pos 54 C00078 HMDB Amino acid Tryptophan metabolism ; serotonin (5HT) LC/MS pos 2342 C00780 HMDB Amino acid Tryptophan metabolism ; C-glycosyltryptophan* LC/MS pos Amino acid Tryptophan metabolism beta-hydroxyisovalerate LC/MS neg HMDB Amino acid Valine, leucine and isoleucine metabolism ; isoleucine LC/MS pos 1125 C00407 HMDB Amino acid Valine, leucine and isoleucine metabolism ; leucine LC/MS pos 60 C00123 HMDB Amino acid Valine, leucine and isoleucine metabolism ; N-acetylvaline LC/MS pos 1591 HMDB Amino acid Valine, leucine and isoleucine metabolism ; valine LC/MS pos 1649 C00183 HMDB Amino acid Valine, leucine and isoleucine metabolism ; alpha-hydroxyisovalerate GC/MS HMDB Amino acid Valine, leucine and isoleucine metabolism ; isobutyrylcarnitine LC/MS pos < Amino acid Valine, leucine and isoleucine metabolism ; methylbutyroylcarnitine LC/MS pos HMDB Amino acid Valine, leucine and isoleucine metabolism ; isovalerylcarnitine LC/MS pos HMDB Amino acid Valine, leucine and isoleucine metabolism cysteine GC/MS C00097 HMDB Amino acid Cysteine, methionine, SAM, taurine metabolism ; ; S-methylcysteine GC/MS HMDB Amino acid Cysteine, methionine, SAM, taurine metabolism ; cystine GC/MS C00491 HMDB Amino acid Cysteine, methionine, SAM, taurine metabolism ; cystathionine GC/MS C02291 HMDB Amino acid Cysteine, methionine, SAM, taurine metabolism ; N-formylmethionine LC/MS neg 2829 C03145 HMDB Amino acid Cysteine, methionine, SAM, taurine metabolism ; hypotaurine LC/MS pos 590 C00519 HMDB Amino acid Cysteine, methionine, SAM, taurine metabolism ; taurine GC/MS C00245 HMDB Amino acid Cysteine, methionine, SAM, taurine metabolism ; S-adenosylhomocysteine (SAH) LC/MS neg C00021 HMDB Amino acid Cysteine, methionine, SAM, taurine metabolism ; methionine LC/MS pos 1302 C00073 HMDB Amino acid Cysteine, methionine, SAM, taurine metabolism ; N-acetylmethionine LC/MS neg 1589 C02712 HMDB Amino acid Cysteine, methionine, SAM, taurine metabolism ; hydroxybutyrate (AHB) GC/MS C05984 HMDB Amino acid Cysteine, methionine, SAM, taurine metabolism ; homocysteine GC/MS C00155 HMDB Amino acid Cysteine, methionine, SAM, taurine metabolism ; dimethylarginine (SDMA + ADMA) LC/MS pos C03626 HMDB01539,HM DB Amino acid Urea cycle; arginine-, proline-, metabolism arginine LC/MS neg 1638 C00062 HMDB Amino acid Urea cycle; arginine-, proline-, metabolism ; ornithine GC/MS 1493 C00077 HMDB Amino acid Urea cycle; arginine-, proline-, metabolism ; urea GC/MS 1670 C00086 HMDB Amino acid Urea cycle; arginine-, proline-, metabolism ; proline LC/MS pos 1898 C00148 HMDB Amino acid Urea cycle; arginine-, proline-, metabolism ; aminovalerate LC/MS pos C00431 HMDB Amino acid Urea cycle; arginine-, proline-, metabolism ; citrulline LC/MS pos 2132 C00327 HMDB Amino acid Urea cycle; arginine-, proline-, metabolism ; N-acetylornithine LC/MS pos C00437 HMDB Amino acid Urea cycle; arginine-, proline-, metabolism ; trans-4-hydroxyproline GC/MS 1366 C01157 HMDB Amino acid Urea cycle; arginine-, proline-, metabolism ; argininosuccinate GC/MS C03406 HMDB Amino acid Urea cycle; arginine-, proline-, metabolism ; creatine LC/MS pos C00300 HMDB Amino acid Creatine metabolism ; creatinine LC/MS pos 513 C00791 HMDB Amino acid Creatine metabolism ; Butanoate metabolism 2-aminobutyrate GC/MS 1577 C02261 HMDB Amino acid Butanoate metabolism ; methylthioadenosine (MTA) LC/MS pos 1419 C00170 HMDB Amino acid Polyamine metabolism ; putrescine GC/MS 1408 C00134 HMDB Amino acid Polyamine metabolism ; N-acetylputrescine LC/MS pos C02714 HMDB Amino acid Polyamine metabolism ; agmatine GC/MS C00179 HMDB Amino acid Polyamine metabolism ; spermidine LC/MS pos 485 C00315 HMDB Amino acid Polyamine metabolism ; guanidinobutanoate LC/MS pos C01035 HMDB Amino acid Guanidino and acetamido metabolism ; ; acetamidobutanoate LC/MS pos 1558 C02946 HMDB Amino acid Guanidino and acetamido metabolism ; glutathione, reduced (GSH) LC/MS pos 2127 C00051 HMDB Amino acid Glutathione metabolism ; oxoproline LC/MS neg 1494 C01879 HMDB Amino acid Glutathione metabolism ; glutathione, oxidized (GSSG) LC/MS pos C00127 HMDB Amino acid Glutathione metabolism ; cysteine-glutathione disulfide LC/MS pos HMDB < Amino acid Glutathione metabolism ; S-lactoylglutathione LC/MS neg C03451 HMDB < Amino acid Glutathione metabolism ; glycylvaline LC/MS pos Peptide Dipeptide ; glycylproline LC/MS pos HMDB Peptide Dipeptide ; glycylisoleucine LC/MS pos Peptide Dipeptide ; glycylleucine LC/MS pos C02155 HMDB Peptide Dipeptide ; glycyltyrosine LC/MS pos Peptide Dipeptide ; alanylalanine GC/MS C00993 HMDB Peptide Dipeptide ; prolylleucine LC/MS pos Peptide Dipeptide ; pro-hydroxy-pro LC/MS pos HMDB Peptide Dipeptide ; valylglutamate LC/MS pos Peptide Dipeptide ; cysteinylglycine GC/MS C01419 HMDB Peptide Dipeptide ; cyclo(leu-pro) LC/MS pos Peptide Dipeptide cyclo(glu-glu) LC/MS pos Peptide Dipeptide aspartylleucine LC/MS pos Peptide Dipeptide ; isoleucylglycine LC/MS pos Peptide Dipeptide ; leucylglycine LC/MS pos Peptide Dipeptide ; serylleucine LC/MS pos Peptide Dipeptide ; gamma-glutamylvaline LC/MS pos HMDB Peptide gamma-glutamyl ; gamma-glutamylleucine LC/MS pos HMDB Peptide gamma-glutamyl ; gamma-glutamylisoleucine* LC/MS pos HMDB Peptide gamma-glutamyl gamma-glutamylglycine GC/MS HMDB Peptide gamma-glutamyl ; gamma-glutamylmethionine LC/MS pos Peptide gamma-glutamyl ; gamma-glutamylglutamate LC/MS pos Peptide gamma-glutamyl ; gamma-glutamylglutamine LC/MS pos 2730 HMDB Peptide gamma-glutamyl ; gamma-glutamylphenylalanine LC/MS pos HMDB Peptide gamma-glutamyl ; gamma-glutamyltyrosine LC/MS pos Peptide gamma-glutamyl ; N-acetylglucosamine GC/MS C00140 HMDB Carbohydrate Aminosugars metabolism ; erythronate* GC/MS HMDB Carbohydrate Aminosugars metabolism ; N-acetylneuraminate GC/MS 1592 C00270 HMDB Carbohydrate Aminosugars metabolism ; Isobar: UDP-acetylglucosamine, UDPacetylgalactosamine LC/MS pos Carbohydrate Aminosugars metabolism fructose GC/MS C00095 HMDB Carbohydrate Fructose, mannose, galactose, starch, and sucrose metabolism ; galactitol (dulcitol) GC/MS 1117 C01697 HMDB Carbohydrate Fructose, mannose, galactose, starch, and sucrose metabolism ; galactose GC/MS C01582 HMDB Carbohydrate Fructose, mannose, galactose, starch, and sucrose metabolism ; '-sialyllactose GC/MS G00265 HMDB Carbohydrate Fructose, mannose, galactose, starch, and sucrose metabolism ; mannitol GC/MS C00392 HMDB Carbohydrate Fructose, mannose, galactose, starch, and sucrose metabolism ; mannose GC/MS 584 C00159 HMDB Carbohydrate Fructose, mannose, galactose, starch, and sucrose metabolism ; mannose-6-phosphate GC/MS 1470 C00275 HMDB Carbohydrate Fructose, mannose, galactose, starch, and sucrose metabolism ; ; stachyose LC/MS neg C01613 HMDB Carbohydrate Fructose, mannose, galactose, starch, and sucrose metabolism ; sorbitol GC/MS C00794 HMDB Carbohydrate Fructose, mannose, galactose, starch, and sucrose metabolism ; sucrose LC/MS neg 1519 C00089 HMDB Carbohydrate Fructose, mannose, galactose, starch, and sucrose metabolism ; raffinose LC/MS neg 586 C00492 HMDB Carbohydrate Fructose, mannose, galactose, starch, and sucrose metabolism ; glycerate GC/MS 1572 C00258 HMDB Carbohydrate Glycolysis, gluconeogenesis, pyruvate metabolism ; glucose-6-phosphate (G6P) GC/MS C00668 HMDB Carbohydrate Glycolysis, gluconeogenesis, pyruvate metabolism ; glucose 1-phosphate GC/MS C00103 HMDB Carbohydrate Glycolysis, gluconeogenesis, pyruvate metabolism ; glucose GC/MS C00293 HMDB Carbohydrate Glycolysis, gluconeogenesis, pyruvate metabolism ; fructose-6-phosphate GC/MS C05345 HMDB Carbohydrate Glycolysis, gluconeogenesis, pyruvate metabolism ; Isobar: fructose 1,6-diphosphate, glucose 1,6- diphosphate, myo-inositol 1,4 or 1,3-diphosphate LC/MS neg Carbohydrate Glycolysis, gluconeogenesis, pyruvate metabolism phosphoglycerate GC/MS C00597 HMDB Carbohydrate Glycolysis, gluconeogenesis, pyruvate metabolism ; dihydroxyacetone phosphate (DHAP) GC/MS C00111 HMDB Carbohydrate Glycolysis, gluconeogenesis, pyruvate metabolism ; ,3-dihydroxyacetone GC/MS C00184 HMDB Carbohydrate Glycolysis, gluconeogenesis, pyruvate metabolism ; phosphoenolpyruvate (PEP) GC/MS 597 C00074 HMDB Carbohydrate Glycolysis, gluconeogenesis, pyruvate metabolism ; lactate GC/MS 527 C00186 HMDB Carbohydrate Glycolysis, gluconeogenesis, pyruvate metabolism ; arabitol GC/MS C00474 HMDB Carbohydrate Nucleotide sugars, pentose metabolism ; ribitol GC/MS C00474 HMDB Carbohydrate Nucleotide sugars, pentose metabolism ; threitol GC/MS C16884 HMDB Carbohydrate Nucleotide sugars, pentose metabolism ; sedoheptulose-7-phosphate GC/MS C05382 HMDB Carbohydrate Nucleotide sugars, pentose metabolism ; ribose GC/MS C00121 HMDB Carbohydrate Nucleotide sugars, pentose metabolism ; ribose 5-phosphate GC/MS 561 C00117 HMDB Carbohydrate Nucleotide sugars, pentose metabolism ; ; ribulose GC/MS C00309 HMDB00621,HM DB Carbohydrate Nucleotide sugars, pentose metabolism ; Isobar: ribulose 5-phosphate, xylulose 5-phosphate GC/MS Carbohydrate Nucleotide sugars, pentose metabolism UDP-glucose GC/MS C00029 HMDB Carbohydrate Nucleotide sugars, pentose metabolism ; UDP-glucuronate GC/MS C00167 HMDB Carbohydrate Nucleotide sugars, pentose metabolism ; ; xylitol GC/MS 4966 C00379 HMDB Carbohydrate Nucleotide sugars, pentose metabolism ; arabinose GC/MS 575 C00181 HMDB Carbohydrate Nucleotide sugars, pentose metabolism ; xylonate GC/MS C00502,C Carbohydrate Nucleotide sugars, pentose metabolism ; xylulose GC/MS C00310 HMDB Carbohydrate Nucleotide sugars, pentose metabolism ; Nucleotide sugars UDP-galactose GC/MS C00052 HMDB Carbohydrate Nucleotide sugars ; ; citrate GC/MS 1564 C00158 HMDB Energy Krebs cycle ; succinate GC/MS 1437 C00042 HMDB Energy Krebs cycle ; fumarate GC/MS 1643 C00122 HMDB Energy Krebs cycle ; malate GC/MS 1303 C00149 HMDB Energy Krebs cycle ; acetylphosphate GC/MS C00227 HMDB Energy Oxidative phosphorylation ; phosphate GC/MS C00009 HMDB Energy Oxidative phosphorylation ; pyrophosphate (PPi) GC/MS 2078 C00013 HMDB Energy Oxidative phosphorylation ; linoleate (18:2n6) LC/MS neg 1105 C01595 HMDB Lipid Essential fatty acid ; linolenate [alpha or gamma; (18:3n3 or 6)] LC/MS neg C06427 HMDB Lipid Essential fatty acid dihomo-linolenate (20:3n3 or n6) LC/MS neg C03242 HMDB Lipid Essential fatty acid eicosapentaenoate (EPA; 20:5n3) LC/MS neg C06428 HMDB Lipid Essential fatty acid ; ; docosapentaenoate (n3 DPA; 22:5n3) LC/MS neg C16513 HMDB Lipid Essential fatty acid ; docosapentaenoate (n6 DPA; 22:5n6) LC/MS neg C06429 HMDB Lipid Essential fatty acid ; docosahexaenoate (DHA; 22:6n3) LC/MS neg C06429 HMDB Lipid Essential fatty acid ; caprylate (8:0) LC/MS neg C06423 HMDB Lipid Medium chain fatty acid ; pelargonate (9:0) LC/MS neg C01601 HMDB Lipid Medium chain fatty acid ; caprate (10:0) LC/MS neg 1642 C01571 HMDB Lipid Medium chain fatty acid ; laurate (12:0) LC/MS neg 1645 C02679 HMDB Lipid Medium chain fatty acid ; myristate (14:0) LC/MS neg 1365 C06424 HMDB Lipid Long chain fatty acid ; myristoleate (14:1n5) LC/MS neg C08322 HMDB Lipid Long chain fatty acid ; pentadecanoate (15:0) GC/MS 1361 C16537 HMDB Lipid Long chain fatty acid ; palmitate (16:0) LC/MS neg 1336 C00249 HMDB Lipid Long chain fatty acid ; palmitoleate (16:1n7) LC/MS neg C08362 HMDB Lipid Long chain fatty acid ; margarate (17:0) LC/MS neg 1121 HMDB Lipid Long chain fatty acid ; heptadecenoate (17:1n7) LC/MS neg Lipid Long chain fatty acid ; stearate (18:0) LC/MS neg 1358 C01530 HMDB Lipid Long chain fatty acid ; Mean Values % Filled Values THP mir Contr Mec1 mir-125b Mec1 mir Contr Mec2 mir-125b Mec2 mir Contr Mec2 mir Contr Table S5: Heat map of statistically significant biochemicals profiled in this study. For paired comparisons, shaded cells indicate p 0.05 (red indicates that the mean values are significantly higher for that comparison; green values significantly lower). Blue-bolded text indicates 0.05< p< All data normalized using Bradford protein concentration. Fold of Change Statistical Value Welch's Two-Sample t-test Welch's Two-Sample t-test HMDB THP mir-125b THP mir Contr Mec1 mir-125b Mec1 mir Contr Mec2 mir-125b Mec2 mir Contr PATHWAY SORT SUPER PATHWAY SUB PATHWAY BIOCHEMICAL NAME PLATFORM COMP ID KEGG THP mir-125b THP mir-125b / THP mir Contr Mec1 mir-125b / Mec1 mir Contr Mec2 mir-125b / Mec2 mir Contr CAS RI MASS Glycine, serine and threonine metabolism Super Pathway Sub Pathway PUBCHEM Mec1 mir-125b Mec1 mir Contr Mec2 mir-125b THP mir-125b THP mir Contr Guanidino and acetamido metabolism Glutathione metabolism Peptide Dipeptide gamma-glutamyl Carbohydrate Aminosugars metabolism Fructose, mannose, galactose, starch, and sucrose metabolism Glycolysis, gluconeogenesis, pyruvate metabolism Nucleotide sugars, pentose metabolism Amino acid Cysteine, methionine, SAM, taurine metabolism Urea cycle; arginine-, proline-, metabolism Creatine metabolism Polyamine metabolism Tryptophan metabolism Valine, leucine and isoleucine metabolism Alanine and aspartate metabolism Glutamate metabolism Histidine metabolism Lysine metabolism Phenylalanine & tyrosine metabolism Energy Krebs cycle Oxidative phosphorylation Essential fatty acid Medium chain fatty acid Long chain fatty acid

11 639 oleate (18:1n9) GC/MS 1359 C00712 HMDB Lipid Long chain fatty acid ; cis-vaccenate (18:1n7) GC/MS C Lipid Long chain fatty acid ; octadecenoate (18:1n5) GC/MS Lipid Long chain fatty acid ; nonadecenoate (19:1n9) LC/MS neg Lipid Long chain fatty acid ; eicosenoate (20:1n9 or 11) LC/MS neg HMDB Lipid Long chain fatty acid dihomo-linoleate (20:2n6) LC/MS neg C Lipid Long chain fatty acid ; arachidonate (20:4n6) LC/MS neg 1110 C00219 HMDB Lipid Long chain fatty acid ; docosadienoate (22:2n6) LC/MS neg C Lipid Long chain fatty acid ; docosatrienoate (22:3n3) LC/MS neg C16534 HMDB Lipid Long chain fatty acid ; adrenate (22:4n6) LC/MS neg C16527 HMDB Lipid Long chain fatty acid ; Fatty acid, methyl ester methyl stearate GC/MS Lipid Fatty acid, methyl ester ; hydroxybutyrate (GHB) GC/MS C00989 HMDB Lipid Fatty acid, monohydroxy ; hydroxypalmitate LC/MS neg Lipid Fatty acid, monohydroxy ; adipate GC/MS C06104 HMDB Lipid Fatty acid, dicarboxylate ; hydroxyglutarate GC/MS C02630 HMDB Lipid Fatty acid, dicarboxylate ; azelate (nonanedioate) LC/MS neg C08261 HMDB Lipid Fatty acid, dicarboxylate ; oleamide GC/MS HMDB Lipid Fatty acid, amide ; stearamide GC/MS C Lipid Fatty acid, amide ; Fatty acid, branched methyl palmitate (15 or 2) LC/MS neg Lipid Fatty acid, branched oleic ethanolamide LC/MS neg HMBD Lipid Endocannabinoid ; ; palmitoyl ethanolamide LC/MS neg Lipid Endocannabinoid stearoyl ethanolamide LC/MS pos Lipid Endocannabinoid ; propionylcarnitine LC/MS pos C03017 HMDB Lipid Fatty acid metabolism (also BCAA metabolism) ; butyrylcarnitine LC/MS pos < Lipid Fatty acid metabolism (also BCAA metabolism) ; deoxycarnitine LC/MS pos C01181 HMDB Lipid Carnitine metabolism ; carnitine LC/MS pos Lipid Carnitine metabolism ; dehydrocarnitine* LC/MS pos C02636 HMDB Lipid Carnitine metabolism ; acetylcarnitine LC/MS pos C02571 HMDB < < Lipid Carnitine metabolism ; palmitoylcarnitine LC/MS pos Lipid Carnitine metabolism ; stearoylcarnitine LC/MS pos HMDB Lipid Carnitine metabolism ; oleoylcarnitine LC/MS pos HMDB Lipid Carnitine metabolism glycocholate LC/MS neg C01921 HMDB Lipid Bile acid metabolism ; ; taurocholate LC/MS neg C05122 HMDB Lipid Bile acid metabolism ; taurochenodeoxycholate LC/MS neg C05465 HMDB Lipid Bile acid metabolism ; deoxycholate LC/MS neg 1114 C04483 HMDB < Lipid Bile acid metabolism ; taurodeoxycholate LC/MS neg C05463 HMDB Lipid Bile acid metabolism ; glycochenodeoxycholate LC/MS neg C05466 HMDB Lipid Bile acid metabolism ; Fatty alcohol, long chain 1-octadecanol GC/MS D01924 HMDB Lipid Fatty alcohol, long chain ; choline phosphate LC/MS pos < Lipid Glycerolipid metabolism ; ethanolamine GC/MS 1497 C00189 HMDB Lipid Glycerolipid metabolism ; phosphoethanolamine GC/MS C00346 HMDB Lipid Glycerolipid metabolism ; glycerophosphoethanolamine GC/MS C01233 HMDB Lipid Glycerolipid metabolism ; glycerol 3-phosphate (G3P) GC/MS C00093 HMDB Lipid Glycerolipid metabolism ; glycerophosphorylcholine (GPC) LC/MS pos C00670 HMDB < Lipid Glycerolipid metabolism ; cytidine 5'-diphosphocholine LC/MS pos Lipid Glycerolipid metabolism ; cytidine-5'-diphosphoethanolamine LC/MS pos C00570 HMDB Lipid Glycerolipid metabolism ; myo-inositol GC/MS C00137 HMDB Lipid Inositol metabolism ; chiro-inositol GC/MS Lipid Inositol metabolism ; inositol 1-phosphate (I1P) GC/MS 1481 HMDB Lipid Inositol metabolism ; scyllo-inositol GC/MS C06153 HMDB Lipid Inositol metabolism ; palmitoylglycerophosphoethanolamine LC/MS neg HMDB Lipid Lysolipid palmitoylglycerophosphoethanolamine* LC/MS pos < Lipid Lysolipid palmitoleoylglycerophosphoethanolamine* LC/MS neg Lipid Lysolipid palmitoleoylglycerophosphoethanolamine* LC/MS pos Lipid Lysolipid stearoylglycerophosphoethanolamine LC/MS pos HMDB Lipid Lysolipid ; oleoylglycerophosphoethanolamine LC/MS neg HMDB Lipid Lysolipid oleoylglycerophosphoethanolamine* LC/MS neg Lipid Lysolipid linoleoylglycerophosphoethanolamine* LC/MS pos Lipid Lysolipid arachidonoylglycerophosphoethanolamine* LC/MS neg HMDB Lipid Lysolipid arachidonoylglycerophosphoethanolamine* LC/MS neg Lipid Lysolipid docosapentaenoylglycerophosphoethanolamine* LC/MS pos Lipid Lysolipid docosahexaenoylglycerophosphoethanolamine* LC/MS pos Lipid Lysolipid stearoylglycerophosphoglycerol LC/MS neg Lipid Lysolipid myristoylglycerophosphocholine LC/MS pos HMDB Lipid Lysolipid ; myristoylglycerophosphocholine* LC/MS pos Lipid Lysolipid pentadecanoylglycerophosphocholine* LC/MS pos < Lipid Lysolipid palmitoylglycerophosphocholine LC/MS pos Lipid Lysolipid ; palmitoylglycerophosphocholine* LC/MS pos Lipid Lysolipid palmitoleoylglycerophosphocholine* LC/MS pos Lipid Lysolipid palmitoleoylglycerophosphocholine* LC/MS pos Lipid Lysolipid heptadecanoylglycerophosphocholine LC/MS pos HMDB Lipid Lysolipid ; stearoylglycerophosphocholine LC/MS pos Lipid Lysolipid ; stearoylglycerophosphocholine* LC/MS pos Lipid Lysolipid oleoylglycerophosphocholine LC/MS pos Lipid Lysolipid ; oleoylglycerophosphocholine* LC/MS pos Lipid Lysolipid linoleoylglycerophosphocholine LC/MS pos C Lipid Lysolipid linoleoylglycerophosphocholine* LC/MS pos Lipid Lysolipid eicosatrienoylglycerophosphocholine* LC/MS pos Lipid Lysolipid eicosatrienoylglycerophosphocholine* LC/MS pos Lipid Lysolipid arachidonoylglycerophosphocholine* LC/MS pos Lipid Lysolipid docosapentaenoylglycerophosphocholine* LC/MS pos Lipid Lysolipid docosapentaenoylglycerophosphocholine* LC/MS pos Lipid Lysolipid docosahexaenoylglycerophosphocholine* LC/MS pos Lipid Lysolipid palmitoylglycerophosphoinositol* LC/MS neg Lipid Lysolipid stearoylglycerophosphoinositol LC/MS neg Lipid Lysolipid oleoylglycerophosphoinositol* LC/MS neg Lipid Lysolipid arachidonoylglycerophosphoinositol* LC/MS neg Lipid Lysolipid arachidonoylglycerophosphoinositol* LC/MS neg Lipid Lysolipid oleoylglycerophosphoinositol* LC/MS neg Lipid Lysolipid oleoylglycerophosphoserine LC/MS neg Lipid Lysolipid oleoylglycerophosphoserine* LC/MS neg Lipid Lysolipid palmitoylplasmenylethanolamine* LC/MS neg Lipid Lysolipid palmitoylglycerol (1-monopalmitin) GC/MS Lipid Monoacylglycerol ; palmitoylglycerol (2-monopalmitin) GC/MS Lipid Monoacylglycerol ; stearoylglycerol (1-monostearin) GC/MS D Lipid Monoacylglycerol ; oleoylglycerol (1-monoolein) GC/MS HMDB Lipid Monoacylglycerol ; oleoylglycerol (2-monoolein) GC/MS Lipid Monoacylglycerol ; Diacylglycerol 1,3-dipalmitoylglycerol GC/MS Lipid Diacylglycerol ; sphinganine LC/MS pos C00836 HMDB Lipid Sphingolipid ; sphingosine LC/MS pos C00319 HMDB Lipid Sphingolipid ; palmitoyl sphingomyelin GC/MS Lipid Sphingolipid stearoyl sphingomyelin GC/MS C00550 HMDB Lipid Sphingolipid ; ; lathosterol GC/MS C01189 HMDB Lipid Sterol/Steroid ; cholesterol GC/MS 63 C00187 HMDB Lipid Sterol/Steroid ; dehydrocholesterol GC/MS C01164 HMDB Lipid Sterol/Steroid ; alpha-hydroxycholesterol GC/MS C03594 HMDB Lipid Sterol/Steroid ; beta-hydroxycholesterol GC/MS C03594 HMDB Lipid Sterol/Steroid ; xanthine GC/MS 3147 C00385 HMDB Nucleotide Purine metabolism, (hypo)xanthine/inosine containing ; xanthosine LC/MS pos C01762 HMDB Nucleotide Purine metabolism, (hypo)xanthine/inosine containing ; xanthosine 5'-monophosphate (xmp) LC/MS pos C00655 HMDB Nucleotide Purine metabolism, (hypo)xanthine/inosine containing ; hypoxanthine LC/MS neg 3127 C00262 HMDB Nucleotide Purine metabolism, (hypo)xanthine/inosine containing ; inosine LC/MS neg Nucleotide Purine metabolism, (hypo)xanthine/inosine containing ; '-deoxyinosine LC/MS neg C05512 HMDB Nucleotide Purine metabolism, (hypo)xanthine/inosine containing ; inosine 5'-monophosphate (IMP) LC/MS pos 2133 C00130 HMDB Nucleotide Purine metabolism, (hypo)xanthine/inosine containing ; adenine LC/MS pos 554 C00147 HMDB Nucleotide Purine metabolism, adenine containing ; adenosine LC/MS pos 555 C00212 HMDB Nucleotide Purine metabolism, adenine containing ; N1-methyladenosine LC/MS pos C02494 HMDB Nucleotide Purine metabolism, adenine containing ; N6-methyladenosine LC/MS pos HMDB Nucleotide Purine metabolism, adenine containing ; '-deoxyadenosine LC/MS pos 1553 C00559 HMDB Nucleotide Purine metabolism, adenine containing ; adenosine 2'-monophosphate (2'-AMP) LC/MS pos C00946 HMDB Nucleotide Purine metabolism, adenine containing ; adenosine 3'-monophosphate (3'-AMP) LC/MS pos C01367 HMDB Nucleotide Purine metabolism, adenine containing ; adenosine 5'-monophosphate (AMP) LC/MS pos C00020 HMDB Nucleotide Purine metabolism, adenine containing ; adenosine 5'-diphosphate (ADP) LC/MS pos 3108 C00008 HMDB Nucleotide Purine metabolism, adenine containing ; adenylosuccinate LC/MS pos C03794 HMDB Nucleotide Purine metabolism, adenine containing ; guanine LC/MS pos C00242 HMDB Nucleotide Purine metabolism, guanine containing ; guanosine LC/MS neg 1573 C00387 HMDB Nucleotide Purine metabolism, guanine containing ; '-deoxyguanosine LC/MS neg 1411 C00330 HMDB Nucleotide Purine metabolism, guanine containing ; guanosine 5'- monophosphate (5'-GMP) LC/MS pos Nucleotide Purine metabolism, guanine containing ; guanosine 5'-diphospho-fucose LC/MS neg Nucleotide Purine metabolism, guanine containing ; N1-methylguanosine LC/MS pos HMDB Nucleotide Purine metabolism, guanine containing ; N2-methylguanosine LC/MS pos HMDB Nucleotide Purine metabolism, guanine containing ; N6-carbamoylthreonyladenosine LC/MS pos Nucleotide Purine metabolism, guanine containing ; urate GC/MS 1604 C00366 HMDB Nucleotide Purine metabolism, urate metabolism ;120K5305; allantoin GC/MS 1107 C02350 HMDB Nucleotide Purine metabolism, urate metabolism ; cytidine LC/MS pos 514 C00475 HMDB Nucleotide Pyrimidine metabolism, cytidine containing ; cytidine 5'-monophosphate (5'-CMP) LC/MS pos 2372 C00055 HMDB < Nucleotide Pyrimidine metabolism, cytidine containing ; '-deoxycytidine LC/MS pos C00881 HMDB Nucleotide Pyrimidine metabolism, cytidine containing ; cytosine GC/MS 573 C00380 HMDB Nucleotide Pyrimidine metabolism, cytidine containing ; Pyrimidine metabolism, orotate containing orotate GC/MS 1505 C00295 HMDB Nucleotide Pyrimidine metabolism, orotate containing ; thymine GC/MS 604 C00178 HMDB Nucleotide Pyrimidine metabolism, thymine containing ; thymidine LC/MS neg C00214 HMDB Nucleotide Pyrimidine metabolism, thymine containing ; thymidine 5'-monophosphate LC/MS neg C00364 HMDB Nucleotide Pyrimidine metabolism, thymine containing ; uracil GC/MS 605 C00106 HMDB Nucleotide Pyrimidine metabolism, uracil containing ; uridine LC/MS neg 606 C00299 HMDB Nucleotide Pyrimidine metabolism, uracil containing ; pseudouridine LC/MS neg C02067 HMDB Nucleotide Pyrimidine metabolism, uracil containing ; methyluridine (ribothymidine) LC/MS neg HMDB Nucleotide Pyrimidine metabolism, uracil containing ; uridine monophosphate (5' or 3') LC/MS neg Nucleotide Pyrimidine metabolism, uracil containing uridine 5'-diphosphate (UDP) LC/MS pos 5345 C00015 HMDB Nucleotide Pyrimidine metabolism, uracil containing ; Purine and pyrimidine metabolism methylphosphate GC/MS Nucleotide Purine and pyrimidine metabolism ; Ascorbate and aldarate metabolism gulono-1,4-lactone GC/MS C01040 HMDB Cofactors and vitamins Ascorbate and aldarate metabolism ; Biotin metabolism biotin LC/MS pos 568 C00120 HMDB Cofactors and vitamins Biotin metabolism ; Folate metabolism 5-methyltetrahydrofolate (5MeTHF) LC/MS neg C00440 HMDB Cofactors and vitamins Folate metabolism ; ; Hemoglobin and porphyrin metabolism heme* LC/MS pos Cofactors and vitamins Hemoglobin and porphyrin metabolism ; nicotinamide LC/MS pos 594 C00153 HMDB Cofactors and vitamins Nicotinate and nicotinamide metabolism ; nicotinamide adenine dinucleotide (NAD+) LC/MS pos 5278 C00003 HMDB Cofactors and vitamins Nicotinate and nicotinamide metabolism ###################### ; nicotinamide adenine dinucleotide reduced (NADH) LC/MS neg C00004 HMDB Cofactors and vitamins Nicotinate and nicotinamide metabolism ; ; nicotinamide riboside* LC/MS pos Cofactors and vitamins Nicotinate and nicotinamide metabolism ; adenosine 5'diphosphoribose LC/MS neg 558 C00301 HMDB Cofactors and vitamins Nicotinate and nicotinamide metabolism ; nicotinate LC/MS neg 1504 C00253 HMDB Cofactors and vitamins Nicotinate and nicotinamide metabolism ; pantothenate LC/MS pos 1508 C00864 HMDB Cofactors and vitamins Pantothenate and CoA metabolism ; phosphopantetheine LC/MS pos C01134 HMDB Cofactors and vitamins Pantothenate and CoA metabolism NA; coenzyme A LC/MS neg 2936 C00010 HMDB Cofactors and vitamins Pantothenate and CoA metabolism ; ; '-dephosphocoenzyme A LC/MS neg C00882 HMDB Cofactors and vitamins Pantothenate and CoA metabolism ; Pyridoxal metabolism pyridoxal LC/MS neg 1651 C00250 HMDB Cofactors and vitamins Pyridoxal metabolism ; flavin adenine dinucleotide (FAD) LC/MS neg 2134 C00016 HMDB Cofactors and vitamins Riboflavin metabolism ; ; riboflavin (Vitamin B2) LC/MS pos 1827 C00255 HMDB Cofactors and vitamins Riboflavin metabolism ; Thiamine metabolism thiamin (Vitamin B1) LC/MS pos Cofactors and vitamins Thiamine metabolism ; Tocopherol metabolism alpha-tocopherol GC/MS 1561 C02477 HMDB Cofactors and vitamins Tocopherol metabolism ; ; pyridoxate LC/MS neg C00847 HMDB Cofactors and vitamins Vitamin B6 metabolism ; pyridoxine (Vitamin B6) LC/MS neg 608 C00314 HMDB Cofactors and vitamins Vitamin B6 metabolism ; hippurate LC/MS neg C01586 HMDB Xenobiotics Benzoate metabolism ; hydroxymandelate GC/MS 1568 C03198 HMDB Xenobiotics Benzoate metabolism ; ; glycerol 2-phosphate GC/MS C02979,D HMDB Xenobiotics Chemical ; HEPES LC/MS neg Xenobiotics Chemical ; Isobar: 2-propylpentanoate, 2-ethylhexanoate LC/MS neg Xenobiotics Chemical phenol red LC/MS neg C Xenobiotics Chemical ; amphotericin B LC/MS neg C Xenobiotics Drug ; penicillin G LC/MS pos C < Xenobiotics Drug ; doxycycline LC/MS neg Xenobiotics Drug ; daidzein LC/MS neg C10208 HMDB Xenobiotics Food component/plant ; homostachydrine* LC/MS pos C Xenobiotics Food component/plant ; Sugar, sugar substitute, starch erythritol GC/MS C00503 HMDB Xenobiotics Sugar, sugar substitute, starch ; Endocannabinoid Fatty acid metabolism (also BCAA metabolism) Carnitine metabolism Bile acid metabolism Glycerolipid metabolism Inositol metabolism Lipid Long chain fatty acid Fatty acid, monohydroxy Fatty acid, dicarboxylate Fatty acid, amide Lysolipid Monoacylglycerol Sphingolipid Sterol/Steroid Nucleotide Purine metabolism, (hypo)xanthine/inosine containing Purine metabolism, adenine containing Purine metabolism, guanine containing Purine metabolism, urate metabolism Pyrimidine metabolism, cytidine containing Xenobiotics Benzoate metabolism Chemical Drug Food component/plant Pyrimidine metabolism, thymine containing Pyrimidine metabolism, uracil containing Cofactors and vitamins Nicotinate and nicotinamide metabolism Pantothenate and CoA metabolism Riboflavin metabolism Vitamin B6 metabolism

12 Table S6: Putative mir-125b target transcripts encoding key enzymes and regulators of metabolism Gene symbol Encoded factor Main role(s) Glycolysis HK2 Hexokinase 2 Glucose -> Glucose-6P (first step of glycolysis) Tricarboxylic acids cycle PDK1 PDK2 PDK3 SLC25A10 / DIC Lipid synthesis Pyruvate dehydrogenase kinase, isozyme 1 Pyruvate dehydrogenase kinase, isozyme 2 Pyruvate dehydrogenase kinase, isozyme 3 Solute carrier family 25 (mitochondrial carrier; dicarboxylate transporter), member 10 Phosphorylates the pyruvate dehydrogenase complex, impairing the oxidative decarboxylation of pyruvate Same as PDK1 Same as PDK1 Transport of dicarboxylates such as malate and succinate across the mitochondrial membranes / Supplying substrates for the TCA cycle, gluconeogenesis, urea synthesis, and sulfur metabolism FADS3 Fatty acid desaturase 3 Regulates unsaturation of fatty acids through introduction of double bonds between defined carbons of the fatty acyl chain SLC27A1 / FATP1 Solute carrier family 27 (fatty acid transporter), member 1 Balances storage with metabolic needs during transitions between fasted and fed states ELOVL6 Fatty acid elongase 6 Uses malonyl-coa as a 2- carbon donor in the first and rate-limiting step of fatty acid Metabolic changes compatible with increased activity in CLL patients with lower mir-125b levels Significant lower levels of glucose and glucose-6-phosphate indicative of increased glucose utilisation ( Warburg effect ) Lower citrate levels consistent with limited entry of glycolytic end products into the TCA cycle Same as PDK1 Same as PDK1 Higher levels of succinate, fumarate and malate, suggesting anaplerotic incorporation of amino acids into the TCA cycle for energy production Higher levels of essential, mediumand long-chain fatty acids, as well as of monoacylglycerols and glycerol, suggesting increased lipolysis to support fatty acid synthesis and membrane remodeling

13 SCD / SCD1 Glutaminolysis Stearoyl-Coenzyme A desaturase 1 elongation Catalyzes a rate-limiting step in the synthesis of unsaturated fatty acids GLS / GLS1 Glutaminase Major enzyme yielding glutamate from glutamine Nucleotide synthesis PPAT Phosphoribosyl pyrophosphate amidotransferase Aminoacid synthesis BCAT1 Branched chain aminoacid transaminase 1, cytosolic Eicosanoid synthesis ALOX5 / 5- LOX Alcool metabolism ALDH3A2 / FALDH / ALDH10 ALDH1B1 / ALDH5 Arachidonate 5- lipoxygenase Aldehyde dehydrogenase 3 family, member A2 Aldehyde dehydrogenase 1 family, member B1 Regulation of the intracellular redox environment. Catalyzes the first step of de novo purine nucleotide biosythetic pathway / Provides purines for FAD(H 2 ), NAD(H), NADP(H), coenzyme A, DNA and RNA biosynthesis Transamination of branchedchain alpha-keto acids to branched-chain L-amino acids / Essential for cell growth Synthesis of leukotrienes, 5- HETE and 12-HETE from arachidonic acid Detoxification of aldehydes generated by alcohol metabolism and lipid peroxidation Upregulated in tumors GSS / GSHS Glutathione synthetase Conversion of gamma-lglutamyl-l-cysteine to glutathione TXNRD1 TXNRD2 Metabolism regulation IGF1R Thioredoxin reductase 1 Thioredoxin reductase 2 Insulin-like growth factor 1 receptor Reduction of the active site disulfide of thioredoxin / Regulation of the intracellular redox environment Same as TXRND1 Tyrosine kinase playing a critical role in AKT / PKB activation and transformation Decreased glutamine levels in patients with aggressive CLL to provide metabolic molecules from glutamate and reductive power for fatty acid biosynthesis by NADPH production by malate dehydrogenase Increased levels of both 5 -AMP and 5 - GMP for DNA synthesis Decreased levels of 12-HETE, possibly due to decreased synthesis or increased secretion of eicosanoids

14 IGFBP3 PIK3IP1 PDPK1 AKT2 / PKBB PPARα / NR1C1 TP53 TPR3INP1 IGF1 Binding protein- 3 Phosphoinositide-3- kinase interacting protein 1 3-phosphoinositide dependent protein kinase-1 v-akt murine thymoma viral oncogene homolog 2 Peroxisome proliferator-activated receptor α Tumor Suppressor protein 53 tumor protein p53 inducible nuclear protein 1 events / Works upstream of PI3 kinase / Responsible for IGF1 anabolic effects Increases IGF1 half-life by allowing it to evade renal clearance Negative regulator of PIK3 Phosphorylation of AKT/PKB kinases Glucose and lipid metabolism Nuclear receptor / Activation of genes encoding proteins implicated in cellular fatty acid uptake, fatty acid oxydation, fatty acid transport into the mitochondrium, ketone body formation and cellular carnithine uptake Powerful anti-tumor factor / Opposes pro-tumor metabolism Tumor suppressor Significant lower levels of glucose and glucose-6-phosphate indicative of increased glucose utilisation ( Warburg effect ) / Higher fatty acid levels Higher levels of essential, mediumand long-chain fatty acids compatible with enhanced fatty acid biosynthesis

15 Figure S1. MiR-125b expression significantly decreases, while that of mir-155 significantly increases in CLL patients compare to purified B cells from healthy donors. (A) - (C). The relative levels of mir-125b (A), mir-155 (B) and mir-125a (C) in CLL patients were determined by qrt-pcr. P values (Student t test) are given for Indolent [n = 6 for (A) and (B), n = 9 for (C)] and Aggressive [n = 6 for (A) and (B), n = 9 for (C)] versus Healthy [n = 6 for (A), (B) and (C)]. Boxes include values from the first to the third quartiles; o, extreme data points; +, median; x, mean ± standard deviation.

16 Figure S2. 17p deletions in IND or AGG CLL has no measurable effects on mir-125b and mir-155 expression. (A), (B). The relative levels of mir-125b (A) and mir-155 (B) in each of the 15 HD as well as in a panel of patients with IND [n=35, of whom 9 with del(17p)] or AGG [n=38, of whom 9 with del(17p)] form of CLL, as indicated, were measured by qrt-pcr. The same data were used for panels A and B of Fig. 1.

17 Figure S3. Transfecting DAUDI cells with 125b-I increases slightly but significantly the expression of luciferase constructs containing PCTP, LIPA or GSS 3 -UTRs. Luciferase assays showing the effects of an antisense mir-125b inhibitory RNA (125b-I) on the expression of luciferase constructs containing the indicated 3 -UTRs in DAUDI cells. Values represent the mean ± standard deviation (n = 4). P values (Student t test) are given for 125b-I versus control. Figure S4. MiR-125b targets transcripts encoding transcription factors of the IKAROS family. Luciferase assays were done in MeG01 cells as previously described 24 using luciferase constructs containing IKZF2, IKZF3 or IKZF4 3 -UTR. Luciferase assays were performed 48 hours following cell transfection. Values represent the mean ± standard deviation (n = 4). P values (student t test) are given for mir-125b versus control.