Supplemental information
Additional methodological details to Figure 3 (main text): Phenotypic analysis of LPL+ B-CLLs
A potential relationship of LPL+ B-CLLto 52 tissues was calculated by ranking relative gene expression across 52 human tissues of LPL+ signature genes. Detailed information regarding source and isolation method of the 52 tissues used for the phenotypic analysis can be obtained from this website: Briefly, we downloaded the respective Affymetrix U133A files (in duplicate for each tissue) followed by normalization using RMA. Next, we filtered out genes with low expression from these 52 tissues to remove noise yielding 5501 genes. Next we inspected these 5501 genes for presence of the LPL+ signature genes (see Supplemental table 1A & B for the 111 genes). Of 111 LPL+ signature genes, 64 genes were contained within these 5501 genes (see Supplemental table 3 for the 64 genes). An index of relative gene expression for each tissue was created by first ranking the expression levels of each gene over all tissues, whereupon rank 52 is given for highest and rank 1 for lowest expression for the tissue of interest. A Mann Whitney rank sum test was then applied comparing the ranks over all 52 tissues. Using this approach fat was the highest ranking tissue with the most discriminating p-value (P=4.9x10-6) followed by skeletal muscle, heart and peripheral blood dendritic cells (P=9.8x10-6, 4.6x10-5, and 7.2x10-4, respectively ) as the most significantly associated tissues. This procedure identified tissues in which these 64 genes are mostly regulated.
Supplemental Table 1A: LPL associated gene expression changes. 67 differentially expressed genes ≥ 1.5fold between LPL+ and LPL- in 20 B-CLL patient samples (n=10 for LPL+ and LPL-, respectively). Fold changes were calculated from the mean signals of the individual samples.
Probe set ID / Symbol / Fold Change LPL+/LPL- / Gene Name / Biological Function211645_x_at / - / 24.2 / Cationic anti-DNA autoantibody / Unknown
212698_s_at / Sept10 / 8.0 / septin 10 / GTP-binding
203548_s_at / LPL / 7.5 / lipoprotein lipase / Lipid meabolism
203881_s_at / DMD / 5.1 / dystrophin / Muscle Development
219496_at / C2orf26 / 4.4 / chromosome 2 open reading frame 26 / Unknown
209598_at / PNMA2 / 4.3 / paraneoplastic antigen MA2 / Nucleus
203549_s_at / LPL / 4.0 / lipoprotein lipase / Lipid meabolism
212503_s_at / KIAA0934 / 3.4 / KIAA0934 / Metabolism
215621_s_at / IGHM / 2.9 / immunoglobulin heavy constant mu / Immune response
204866_at / PHF16 / 2.7 / PHD finger protein 16 / Transcription
213674_x_at / IGHD / 2.7 / immunoglobulin heavy constant delta / Immune response / defense response
203695_s_at / DFNA5 / 2.5 / deafness, autosomal dominant 5 / Perception of sound
201204_s_at / RRBP1 / 2.5 / ribosome binding protein 1 homolog 180kDa (dog) / Protein targeting / signal transduction
210517_s_at / AKAP12 / 2.4 / A kinase (PRKA) anchor protein (gravin) 12 / Signal Transduction (Kinase activity)
204688_at / SGCE / 2.3 / sarcoglycan, epsilon / Muscle Development
212092_at / PEG10 / 2.2 / paternally expressed 10 / Transcription (Nucleic acid binding)
202421_at / IGSF3 / 2.2 / immunoglobulin superfamily, member 3 / Unknown
214971_s_at / SIAT1 / 2.2 / sialyltransferase 1 / Immune response / defense response
208614_s_at / FLNB / 2.1 / filamin B, beta (actin binding protein 278) / Muscle development
212094_at / PEG10 / 2.1 / paternally expressed 10 / Transcription (Nucleic acid binding)
203795_s_at / BCL7A / 2.1 / B-cell CLL/lymphoma 7A / Actin binding
202981_x_at / SIAH1 / 2.0 / seven in absentia homolog 1 (Drosophila) / Apoptosis
203796_s_at / BCL7A / 2.0 / B-cell CLL/lymphoma 7A / Actin binding
213689_x_at / RPL5 / 2.0 / ribosomal protein L5 / Ribosome
218418_s_at / ANKRD25 / 2.0 / ankyrin repeat domain 25 / Unknown
204072_s_at / 13CDNA73 / 2.0 / hypothetical protein CG003 / Unknown
221234_s_at / BACH2 / 2.0 / basic leucine zipper transcription factor 2 / Transcription
201760_s_at / WSB2 / 1.9 / WD repeat and SOCS box-containing 2 / Signal transduction
212838_at / DNMBP / 1.9 / dynamin binding protein / Signal transduction
210279_at / GPR18 / 1.9 / G protein-coupled receptor 18 / Signal transduction
203454_s_at / ATOX1 / 1.9 / ATX1 antioxidant protein 1 homolog (yeast) / Ion transport (response to oxidative stress)
212671_s_at / HLA-DQA1 / 1.9 / major histocompatibility complex, class II, DQ alpha 1 / Immune response / defense response
216044_x_at / - / 1.9 / similar to RIKEN cDNA 2900024C23 / Unknown
217504_at / ABCA6 / 1.9 / ATP-binding cassette, sub-family A (ABC1), member 6 / Transport
208613_s_at / FLNB / 1.8 / filamin B, beta (actin binding protein 278) / Muscle development
203633_at / CPT1A / 1.8 / carnitine palmitoyltransferase 1A (liver) / Lipid metabolism
220146_at / TLR7 / 1.8 / toll-like recepor 7 / Immune response / defense response
204562_at / IRF4 / 1.8 / interferon regulatory factor 4 / Immune response / defense response
212812_at / - / 1.7 / NA / Unknown
218968_s_at / ZFP64 / 1.7 / zinc finger protein 64 homolog (mouse) / Transcription
201710_at / MYBL2 / 1.7 / v-myb myeloblastosis viral oncogene homolog (avian)-like 2 / Anti-apoptosis / transcription
218096_at / LPAAT-e / 1.7 / acid acyltransferase-epsilon / Lipid metabolism
212504_at / KIAA0934 / 1.7 / KIAA0934 / Unknown
205552_s_at / OAS1 / 1.7 / 2',5'-oligoadenylate synthetase 1, 40/46kDa / Immune response / defense response
203406_at / MFAP1 / 1.7 / microfibrillar-associated protein 1 / Exracellular matrix
203404_at / ARMCX2 / 1.7 / armadillo repeat containing, X-linked 2 / Binding
209498_at / CEACAM1 / 1.7 / carcinoembryonic antigen-related cell adhesion molecule 1 / Immune response / defense response
206337_at / CCR7 / 1.6 / chemokine (C-C motif) receptor 7 / Immune response / defense response
202395_at / NSF / 1.6 / N-ethylmaleimide-sensitive factor / Protein transport
205263_at / BCL10 / 1.6 / B-cell CLL/lymphoma 10 / Apoptosis
209854_s_at / KLK2 / 1.6 / kallikrein 2, prostatic / Proteolysis and peptidolysis
212345_s_at / CREB3L2 / 1.6 / cAMP responsive element binding protein 3-like 2 / Transcription
201206_s_at / RRBP1 / 1.6 / ribosome binding protein 1 homolog 180kDa (dog) / Signal transduction
208900_s_at / TOP1 / 1.6 / topoisomerase (DNA) I / DNA topological change
206760_s_at / FCER2 / 1.6 / Fc fragment of IgE, low affinity II, receptor for (CD23A) / Receptor activity
218999_at / FLJ11000 / 1.6 / hypothetical protein FLJ11000 / Unknown
205704_s_at / ATP6V0A2 / 1.6 / ATPase, H+ transporting, lysosomal V0 subunit a isoform 2 / Immune response / defense response
201772_at / OAZIN / 1.6 / ornithine decarboxylase antizyme inhibitor / Polyamine biosynthesis
212110_at / SLC39A14 / 1.6 / solute carrier family 39 (zinc transporter), member 14 / Transport
206759_at / FCER2 / 1.5 / Fc fragment of IgE, low affinity II, receptor for (CD23A) / Receptor activity
218594_at / FLJ10359 / 1.5 / protein BAP28 / Binding
203143_s_at / KIAA0040 / 1.5 / KIAA0040 gene product / Unknown
216724_at / - / 1.5 / NA / Unknown
216607_s_at / CYP51P2 / 1.5 / cytochrome P450, subfamily 51 pseudogene 2 / Electron transport
204513_s_at / ELMO1 / 1.5 / engulfment and cell motility 1 / Cell motility
209455_at / FBXW11 / 1.5 / F-box and WD-40 domain protein 11 / Signal transduction
205484_at / SIT / 1.5 / SHP2-interacting transmembrane adaptor protein / Immune response / defense response
209236_at / SLC23A1 / 1.5 / solute carrier family 23, member 1 / Transport
204972_at / OAS2 / 1.5 / 2'-5'-oligoadenylate synthetase 2, 69/71kDa / Immune response / defense response
212350_at / TBC1D1 / 1.5 / TBC1 (tre-2/USP6, BUB2, cdc16) domain family, member 1 / GTPase activator activity
214908_s_at / TRRAP / 1.5 / transformation/transcription domain-associated protein / Unknown
221551_x_at / SIAT7D / 1.5 / sialyltransferase 7D / Glycosylation
221479_s_at / BNIP3L / 1.5 / BCL2/adenovirus E1B 19kDa interacting protein 3-like / Apoptosis
209193_at / PIM1 / 1.5 / pim-1 oncogene / Signal Transduction
Supplemental Table 1B: LPL associated gene expression changes. 44 differentially expressed genes -.5fold between LPL+ and LPL- in 20 B-CLL patient samples (n=10 for LPL+ and LPL-, respectively). Fold changes were calculated from the mean signals of the individual samples.
Probe set ID / Symbol / Fold Change LPL+/LPL- / Gene Name / Biological Function212476_at / CENTB2 / -1.5 / centaurin, beta 2 / Unknown
209539_at / ARHGEF6 / -1.5 / Rac/Cdc42 guanine nucleotide exchange factor (GEF) 6 / Apoptosis
201300_s_at / PRNP / -1.6 / prion protein (p27-30) / Metabolism
219191_s_at / BIN2 / -1.7 / bridging integrator 2 / Endocytosis
205255_x_at / TCF7 / -1.7 / transcription factor 7 (T-cell specific, HMG-box) / Immune response / defense response
212001_at / SFRS14 / -1.7 / splicing factor, arginine/serine-rich 14 / Nuclear mRNA splicing
212708_at / CASC3 / -1.7 / cancer susceptibility candidate 3 / Unknown
218845_at / DUSP22 / -1.8 / dual specificity phosphatase 22 / Signal transduction
214141_x_at / SFRS7 / -1.9 / splicing factor, arginine/serine-rich 7, 35kDa / RNA splicing
210944_s_at / CAPN3 / -1.9 / calpain 3, (p94) / Muscle development
201473_at / JUNB / -2.0 / jun B proto-oncogene / Transcription
214805_at / EIF4A1 / -2.1 / eukaryotic translation initiation factor 4A, isoform 1 / Translation initiation
204647_at / HOMER3 / -2.1 / homer homolog 3 (Drosophila) / Defense response
216033_s_at / FYN / -2.1 / FYN oncogene related to SRC, FGR, YES / Signal transduction
212232_at / FNBP4 / -2.1 / formin binding protein 4 / Unknown
213737_x_at / - / -2.1 / NA / Unknown
206662_at / GLRX / -2.1 / glutaredoxin (thioltransferase) / Oxireductase activity
215299_x_at / SULT1A1 / -2.2 / sulfotransferase family, cytosolic, 1A, phenol-preferring, member 1 / Transferase activity
212177_at / C6orf111 / -2.2 / chromosome 6 open reading frame 111 / Unknown
210105_s_at / FYN / -2.3 / FYN oncogene related to SRC, FGR, YES / Signal transduction
205383_s_at / Znf288 / -2.3 / zinc finger and BTB domain containing 20 / Transcription
210592_s_at / SAT / -2.3 / spermidine/spermine N1-acetyltransferase / Transferase activity
213158_at / - / -2.4 / NA / Unknown
204286_s_at / PMAIP1 / -2.4 / phorbol-12-myristate-13-acetate-induced protein 1 / Unknown
213988_s_at / SAT / -2.4 / spermidine/spermine N1-acetyltransferase / Transferase activity
208808_s_at / HMGB2 / -2.5 / high-mobility group box 2 / DNA repair
218067_s_at / FLJ10154 / -2.5 / hypothetical protein FLJ10154 / Unknown
203455_s_at / SAT / -2.6 / spermidine/spermine N1-acetyltransferase / Transferase activity
221239_s_at / SPAP1 / -2.7 / SH2 domain containing phosphatase anchor protein 1 / Cell-cell signaling
213931_at / ID2 / -2.7 / inhibitor of DNA binding 2 / Development
213156_at / - / -2.7 / NA / Unknown
219300_s_at / CNTNAP2 / -2.7 / contactin associated protein-like 2 / Cell adhesion
220046_s_at / CCNL1 / -2.8 / cyclin L1 / Cell cycle
214016_s_at / SFPQ / -2.8 / splicing factor proline/glutamine rich / Nuclear mRNA splicing
201631_s_at / IER3 / -2.8 / immediate early response 3 / Anti-apoptosis
204834_at / FGL2 / -3.1 / fibrinogen-like 2 / Fibrinogen complex
204959_at / MNDA / -3.1 / myeloid cell nuclear differentiation antigen / Immune response / defense response
201669_s_at / MARCKS / -3.2 / myristoylated alanine-rich protein kinase C substrate / Cell motility
201012_at / ANXA1 / -3.3 / annexin A1 / Immune response / defense response / lipid metabolism
205821_at / KLRK1 / -3.4 / killer cell lectin-like receptor subfamily K, member 1 / Unknown
219666_at / MS4A6A / -3.5 / membrane-spanning 4-domains, subfamily A, member 6A / Receptor activity
210387_at / HIST1H2BG / -3.7 / histone 1, H2bg / DNA binding
202388_at / RGS2 / -3.9 / regulator of G-protein signalling 2, 24kDa / Signal Transduction
209189_at / FOS / -4.1 / v-fos FBJ murine osteosarcoma viral oncogene homolog / Immune response / defense response
201041_s_at / DUSP1 / -4.1 / dual specificity phosphatase 1 / Signal transduction
201565_s_at / ID2 / -4.1 / inhibitor of DNA binding 2 / Development
203509_at / SORL1 / -4.4 / Sortilin-related receptor / Lipid metabolism
221841_s_at / KLF4 / -6.1 / Kruppel-like factor 4 (gut) / Transcription
Supplemental Table 2: IgVH mutational status associated gene expression changes. 11 differentially expressed genes ≥/1.5fold between 10 Ig-mutated and 10 IgVH-unmutated B-CLL patient samples. Fold changes were calculated from the mean signals of the individual samples. Genes marked gray are also contained within the LPL expression signature.
Probe set ID / Symbol / Fold Change Unmut/Mut / Gene Name / Biological Function212698_s_at / SEPT10 / 8,0 / septin 10 / GTP-binding
203548_s_at / LPL / 7,5 / lipoprotein lipase / Lipid metabolism
219496_at / C2orf26 / 4,4 / chromosome 2 open reading frame 26 / Unknown
203881_s_at / DMD / 4,2 / dystrophin / Muscle Development
203549_s_at / LPL / 3,9 / lipoprotein lipase / Lipid metabolism
212092_at / PEG10 / 2,3 / paternally expressed 10 / Transcription (Nucleic acid binding)
212094_at / PEG10 / 2,2 / paternally expressed 10 / Transcription (Nucleic acid binding)
212841_s_at / PPFIBP2 / -1,6 / liprin beta 2 / DNA binding
209539_at / ARHGEF6 / -1,6 / Rac/Cdc42 guanine nucleotide exchange factor (GEF) 6 / Apoptosis
218845_at / DUSP22 / -1,8 / dual specificity phosphatase 22 / Signal transduction
205383_s_at / Znf288 / -2,3 / zinc finger and BTB domain containing 20 / Transcription
203642_s_at / COBLL1 / -2,4 / COBL-like 1 / Unnown
213156_at / - / -2,4 / NA / Unknown
Supplemental Table 3:LPL+ signature genes used to perform phenotypic analysis. Following filtering to remove genes with low expression , 64 out of the 110 LPL signature genes were used to perform the phenotypic analysis (see also Supplemental Fig 1).
ID / SYMBOL / Gene Title203549_s_at / LPL / lipoprotein lipase
212503_s_at / KIAA0934 / KIAA0934
201204_s_at / RRBP1 / ribosome binding protein 1 homolog 180kDa (dog)
210517_s_at / AKAP12 / A kinase (PRKA) anchor protein (gravin) 12
204688_at / SGCE / sarcoglycan, epsilon
212092_at / PEG10 / paternally expressed 10
202421_at / IGSF3 / immunoglobulin superfamily, member 3
208614_s_at / FLNB / filamin B, beta (actin binding protein 278)
203795_s_at / BCL7A / B-cell CLL/lymphoma 7A
213689_x_at / RPL5 / ribosomal protein L5
218418_s_at / ANKRD25 / ankyrin repeat domain 25
201760_s_at / WSB2 / WD repeat and SOCS box-containing 2
203454_s_at / ATOX1 / ATX1 antioxidant protein 1 homolog (yeast)
212671_s_at / HLA-DQA1 / major histocompatibility complex, class II, DQ alpha 1
203633_at / CPT1A / carnitine palmitoyltransferase 1A (liver)
212504_at / KIAA0934 / KIAA0934
203406_at / MFAP1 / microfibrillar-associated protein 1
202395_at / NSF / N-ethylmaleimide-sensitive factor
212345_s_at / CREB3L2 / cAMP responsive element binding protein 3-like 2
201206_s_at / RRBP1 / ribosome binding protein 1 homolog 180kDa (dog)
218999_at / FLJ11000 / hypothetical protein FLJ11000
212110_at / SLC39A14 / solute carrier family 39 (zinc transporter), member 14
204513_s_at / ELMO1 / engulfment and cell motility 1 (ced-12 homolog, C. elegans)
209455_at / FBXW11 / F-box and WD-40 domain protein 11
204972_at / OAS2 / 2'-5'-oligoadenylate synthetase 2, 69/71kDa
212350_at / TBC1D1 / TBC1 (tre-2/USP6, BUB2, cdc16) domain family, member 1
221479_s_at / BNIP3L / BCL2/adenovirus E1B 19kDa interacting protein 3-like
209193_at / PIM1 / pim-1 oncogene
207169_x_at / DDR1 / discoidin domain receptor family, member 1
202236_s_at / SLC16A1 / solute carrier family 16 (monocarboxylic acid transporters), member 1
209539_at / ARHGEF6 / Rac/Cdc42 guanine nucleotide exchange factor (GEF) 6
201300_s_at / PRNP / prion protein (p27-30) (
205255_x_at / TCF7 / transcription factor 7 (T-cell specific, HMG-box)
212001_at / SFRS14 / splicing factor, arginine/serine-rich 14
212708_at / CASC3 / cancer susceptibility candidate 3
218845_at / DUSP22 / dual specificity phosphatase 22
214141_x_at / SFRS7 / splicing factor, arginine/serine-rich 7, 35kDa
210944_s_at / CAPN3 / calpain 3, (p94)
201473_at / JUNB / jun B proto-oncogene
214805_at / EIF4A1 / eukaryotic translation initiation factor 4A, isoform 1
216033_s_at / FYN / FYN oncogene related to SRC, FGR, YES
212232_at / FNBP4 / formin binding protein 4
213737_x_at / 213737_x_at / NA
206662_at / GLRX / glutaredoxin (thioltransferase)
215299_x_at / SULT1A1 / sulfotransferase family, cytosolic, 1A, phenol-preferring, member 1
210105_s_at / FYN / FYN oncogene related to SRC, FGR, YES
205383_s_at / Znf288 / zinc finger and BTB domain containing 20
210592_s_at / SAT / spermidine/spermine N1-acetyltransferase
213988_s_at / SAT / spermidine/spermine N1-acetyltransferase
208808_s_at / HMGB2 / high-mobility group box 2
218067_s_at / FLJ10154 / hypothetical protein FLJ10154
203455_s_at / SAT / spermidine/spermine N1-acetyltransferase
220046_s_at / CCNL1 / cyclin L1
214016_s_at / SFPQ / splicing factor proline/glutamine rich (polypyrimidine tract binding protein associated)
201631_s_at / IER3 / immediate early response 3
201669_s_at / MARCKS / myristoylated alanine-rich protein kinase C substrate
201012_at / ANXA1 / annexin A1
205821_at / KLRK1 / killer cell lectin-like receptor subfamily K, member 1
219666_at / MS4A6A / membrane-spanning 4-domains, subfamily A, member 6A
202388_at / RGS2 / regulator of G-protein signalling 2, 24kDa
209189_at / FOS / v-fos FBJ murine osteosarcoma viral oncogene homolog
201041_s_at / DUSP1 / dual specificity phosphatase 1
201565_s_at / ID2 / inhibitor of DNA binding 2, dominant negative helix-loop-helix protein
221841_s_at / KLF4 / Kruppel-like factor 4 (gut)
Supplemental Table 4: Summary of GSEA results. Shown are functional gene sets with P < 0.05.
1Normalized enrichment score to account for the size of the set.
2The nominal P value represents the statistical significance of the ES.
3Control the ratio of false positives to the total number of gene sets attaining a fixed level of significance separately for positive (negative) NES(S) and NES(S, ).