Supplemental Figure S1. Gene Granta-519 MAVER-1 JeKo-1 Mino Z-138 ATM

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Presentation transcript:

Supplemental Figure S1. Gene Granta-519 MAVER-1 JeKo-1 Mino Z-138 ATM BIRC3 BTK CARD11 CDKN2A IKBKB NOTCH1 RB TP53 TRAF2 WHSC1

A B C Supplemental Figure S2 Z138 - + - - + - + Z138 BRD4 BRD2 β-Actin 500 nM, OTX015 500 nM, ARV-825 500 nM, ARV-771 Z138 BRD4 BRD2 β-Actin B MAVER-1 - + - - + - + 500 nM OTX015 500 nM ARV-825 500 nM ARV-771 MAVER-1 BRD4 BRD2 β-Actin Relative Band Intensity C Granta-519 - + - - + - + 500 nM OTX015 500 nM ARV-825 500 nM ARV-771 Granta-519 BRD4 BRD2 β-Actin Relative Band Intensity

Supplemental Figure S3 A % apoptosis μM, Ibrutinib, 48 hr B C

D E F Supplemental Figure S3 MAVER-1 % apoptosis nM, 48 hr Granta-519

Supplemental Table S2 Cell line OTX015 IC50 ARV-825 ARV-771 Mino 398 ± 15 nM 16 ± 3 nM 17 ± 7 nM Z138 >5000 nM 327 ± 23 nM 142 ± 6 nM JeKo-1 >2000 nM 330 nM

Supplemental Table S3 % non-viable cells OTX015 (nM) MCL1 MCL2 MCL3 MCL4 MCL5 MCL6 MCL7 Control 9.8 9.6 11.05 9.4 8.4 9.25 50 22.9 12.7 7.15 13.8 11.1 10.85 100 25.4 15.3 9.9 12.15 14.15 11.7 13.3 250 28.3 15.6 10.2 21.95 21.8 9.1 15.95 % non-viable cells ARV-825 (nM) MCL1 MCL2 MCL3 MCL4 MCL5 MCL6 MCL7 Control 9.8 9.6 11.05 9.4 8.4 9.25 50 24 34.8 13 45.7 23.75 20.6 53.8 100 23.7 39.3 12.1 46.55 27.95 24.8 55.8 250 26.6 40.6 18.3 52.2 29.15 19.9 55.7 % non-viable cells ARV-771 (nM) MCL1 MCL2 MCL3 MCL4 MCL5 MCL6 MCL7 Control 9.8 9.6 11.05 9.4 8.4 9.25 50 23.5 38.4 18.3 45.7 34.55 18.1 43.35 100 24.8 43.8 46.55 44.65 21 47.7 250 25.7 50.9 17 52.2 43.4 22.8 52.7

Supplemental Figure S4 Control Mino TO-PRO-3 iodide Side Scatter Forward Scatter Annexin V (FITC) 20 nM OTX015 50 nM OTX015 100 nM OTX015 200 nM OTX015 500 nM OTX015 20 nM ARV-825 50 nM ARV-825 100 nM ARV-825 200 nM ARV-825 500 nM ARV-825 20 nM ARV-771 50 nM ARV-771 100 nM ARV-771 200 nM ARV-771 500 nM ARV-771

Supplemental Figure S5 A B † † † * * *

Supplemental Table S4. Genes includes on the Illumina L-300 liquid panel. Note: Light blue text indicates that liquid panel includes all coding exons and promoter region ABCC9 BRCA1 CHEK1 DNMT3B FAT3 HIST1H3D KIT MIR21 NSD2 RAD21 SGK1 TET2 ZMYM2 ABL1 BRCA2 CHK2 EBF1 FBXW7 HIST1H4D KLHL6 MIR34B NT5C2 RAD51 SH2B3 TGDS ZMYM3 ACTG1 BRIP1 CIITA ECT2L FGFR3 HNRNPK KRAS MIR34C PAG1 RAD51C SHH TINF2 (TIN2) ZRSR2 AKT1 BTG1 CNOT3 EED FLI1 HRAS LAMB4 MLL PALB2 RAG1 SMAD2 TLR2 ANKRD11 BTK CREBBP EGR1 FLT3 ICOS LEF1 MLL2 PAX5 RAG2 SMC1A TLR9 ARID1A BTLA CRLF2 EGR2 FNDC3A ID3 LRP1B MLL3 PDCD1 RASA2 SMC3 TNFAIP3 ARID1B C22orf194 CSF2RA ELANE FOXP1 IDH1 LTB MPL PDCD1LG2 RB1 SMC5 TNFRSF14 ARID2 CALR CSF3R EP300 FYN IDH2 LUC7L2 MRE11A PDGFRB REL SNX7 TNKS ARID5B CARD11 CTBP1 EPHA7 G6PC3 IKBKA LYN MS4A1 PEG3 RELA SOCS1 TOX ARPP21 CBL CTBP2 EPOR GAB2 IKZF1 MALT1 MYB PHF6 RELB SOX5 TP53 ASXL1 CBLB CTCF ERG GATA1 IKZF2 MAP2K1 MYD88 PHIP RELN SP140 TRAF2 ATF7IP CCND1 CTLA4 ETV6 GATA2 IKZF3 MAP3K14 NBN PIGA RHOA SPEN TRAF3 ATM CCND3 CTNNA1 EZH2 GATA3 IL7R MAPK1 NCOR1 PIK3CA RIPK1 SPIB TRAF6 ATRX CD200 CUL5 FAM46C GCET2 IRAK1 MAX NCOR2 PIK3CB ROBO1 SRSF2 TYK2 B2M CD274 CUX1 FAM5C GFI1B IRAK4 MDM2 NF1 PIK3CG ROR1 STAG1 TYK3 BCL10 CD58 CYLD FANCA GNA13 IRF1 MED12 NFE2 PIK3R1 RPL10 STAG2 U2AF1 BCL2 CD79A DAXX FANCB GNAS IRF4 MEF2B NFKB1 PLA2G2D RPL5 STAT1 U2AF2 BCL6 CD79B DCLRE1C FANCC GNB1 IRF7 MEF2C NFKB2 PLCG2 RUNX1 STAT3 UBR5 BCL7A CDK4 DDX3X FANCD2 GPRC5A ITPKB MGA NFKBIA POT1 RUNX2 SUZ12 USP29 BCOR CDKN2A DIS3 FANCE H2AFX JAK1 MIR125a NFKBIE POU2AF1 SAMHD1 SYK VPREB1 BCR CDKN2B DKC1 FANCG HAX1 JAK2 MIR-142 NOTCH1 PRDM1 SETBP1 TBL1XR1 WHSC1 BIRC3 CDKN2C DLC1 FANCI HIST1H1E JAK3 MIR155 NOTCH2 PRKCB SETD2 TCF3 WHSC1L1 BLK CEBPA DNM2 FANCL HIST1H2AD JARID2 MIR15a NPM1 PTEN SF3B1 TERC WT1 BMI1 CEBPE DNMT1 FAS HIST1H2BE KDM4C MIR16-1 NR3C2 PTPN1 SFRS1 TERT XPO1 BRAF CHD2 DNMT3A FAT1 HIST1H2BF KDM6A MIR17HG NRAS PTPN11 SFRS7 TET1 ZAP70

A B Supplemental Figure S6 % apoptosis nM, OTX015, 48 hrs Mino nM, ARV-825, 48 hrs

A B Supplemental Figure S7 Mino Control ARV-771, 4 hrs 1607 down Gene Log2 Fold Change ARV771/Control P-value MYC -5.24 1.25 e-05 BCL2 0.15 N.S. BCL2L1 -0.61 0.023 BTK -0.27 0.064 PRDM1 -3.8 0.013 BIRC3 -2.33 0.004 BMI1 -0.49 CDKN1A -0.77 0.006 PMAIP (NOXA) -0.71 0.02 HEXIM1 -0.68 0.001

Log2 Fold Change ARV-825/Control Log2 Fold Change OTX015/Control Supplemental Table S5 Gene Log2 Fold Change ARV-825/Control P-Value adj. P-Value Log2 Fold Change OTX015/Control P-value MYC -3.8 9.702E-07 7.08436E-05 -2.81 3.933E-07 4.53317E-05 BCL2 -0.32 0.095631 0.181259708 -0.48 0.0378897 0.098750205 BCL2L1 -1.47 0.0006769 0.005447475 -1.18 0.0003622 0.004863178 BTK -0.35 0.0005819 0.004958887 -0.47 0.0001969 0.00354165 PRDM1 -2.44 2.807E-05 0.000942011 -1.42 0.0014239 0.010607359 TNFAIP3 1.53 5.262E-05 0.001377663 0.69 0.0168286 0.054275476 PMAIP1 1.15 0.0002426 0.003139334 0.62 0.0019832 0.013012155 HEXIM1 2.16 1.817E-07 1.46303E-05 2.36 2.756E-07 3.22739E-05 CDKN1A 0.95 0.0005476 0.004789806 0.72 0.000618 0.006554919 Remove BMI

Remove transcription box totally Supplemental Table S6 GSEA with REACTOME pathways ARV-825 OTX015 REACTOME_SIGNALING_BY_THE_B_CELL_RECEPTOR_BCR 1.853312 1.758218 REACTOME_GPCR_DOWNSTREAM_SIGNALING 7.629242 6.948373 REACTOME_SIGNALING_BY_GPCR 7.386049 6.653636 REACTOME_SIGNALING_BY_EGFR_IN_CANCER 3.114745 2.802434 REACTOME_SIGNALING_BY_FGFR 3.073514 2.517606 REACTOME_DOWNSTREAM_SIGNAL_TRANSDUCTION 3.008598 2.160324 REACTOME_PI_3K_CASCADE 2.735309 2.511638 REACTOME_PI3K_AKT_ACTIVATION 1.99725 1.717785 REACTOME_METABOLISM_OF_AMINO_ACIDS_AND_DERIVATIVES 2.701227 1.866106 REACTOME_RESPIRATORY_ELECTRON_TRANSPORT 2.652065 3.385031 REACTOME_CHROMOSOME_MAINTENANCE 3.972936 REACTOME_TELOMERE_MAINTENANCE 3.975392 1.403697 REACTOME_DNA_REPAIR 1.931087 1.453323 REACTOME_CELL_CYCLE 4.574957 3.309318 REACTOME_CELL_CYCLE_MITOTIC 3.223331 3.485706 REACTOME_CELL_CYCLE_CHECKPOINTS 2.269384 1.982788 REACTOME_G1_S_TRANSITION 2.262535 2.280772 Cell Signaling/ Signal Transduction Metabolism/ electron transport Chromatin Cell Cycle Remove transcription box totally

Supplemental Table S7 Transcription/ Translation Metabolism/ GSEA with REACTOME pathways ARV-825 OTX015 REACTOME_METABOLISM_OF_RNA -3.86177 -3.37222 REACTOME_METABOLISM_OF_MRNA -3.50762 -2.90097 REACTOME_TRANSLATION -3.39158 -3.16636 REACTOME_PROCESSING_OF_CAPPED_INTRON_CONTAINING_PRE_MRNA -3.2026 -3.06745 REACTOME_MITOCHONDRIAL_PROTEIN_IMPORT -3.18342 -2.67806 REACTOME_MRNA_PROCESSING -3.14962 -3.00213 REACTOME_MRNA_SPLICING -2.86363 -2.69898 REACTOME_RNA_POL_III_TRANSCRIPTION -2.63017 -1.72795 REACTOME_RNA_POL_III_TRANSCRIPTION_INITIATION_FROM_TYPE_2_PROMOTER -2.49626 -1.83753 REACTOME_TRANSPORT_OF_MATURE_TRANSCRIPT_TO_CYTOPLASM -2.09126 -1.97615 REACTOME_CLEAVAGE_OF_GROWING_TRANSCRIPT_IN_THE_TERMINATION_REGION -2.08317 -2.05853 REACTOME_RNA_POL_III_TRANSCRIPTION_TERMINATION -2.06825 -1.8907 REACTOME_DEADENYLATION_DEPENDENT_MRNA_DECAY -2.0531 -2.52872 REACTOME_METABOLISM_OF_NON_CODING_RNA -2.45965 -2.70048 REACTOME_APC_C_CDH1_MEDIATED_DEGRADATION_OF_CDC20_AND_OTHER_APC_C_CDH1_TARGETED_PROTEINS_IN_LATE_MITOSIS_EARLY_G1 -2.23118 -1.86285 REACTOME_TRANSPORT_OF_GLUCOSE_AND_OTHER_SUGARS_BILE_SALTS_AND_ORGANIC_ACIDS_METAL_IONS_AND_AMINE_COMPOUNDS -2.22295 -2.66697 REACTOME_APC_C_CDC20_MEDIATED_DEGRADATION_OF_MITOTIC_PROTEINS -2.16804 -1.83439 REACTOME_PURINE_RIBONUCLEOSIDE_MONOPHOSPHATE_BIOSYNTHESIS -2.12728 -2.0343 REACTOME_METABOLISM_OF_PROTEINS -3.2996 -3.06909 REACTOME_SLC_MEDIATED_TRANSMEMBRANE_TRANSPORT -2.68974 -3.45645 REACTOME_GLUCURONIDATION -2.67288 -2.99149 Transcription/ Translation Metabolism/ electron transport

B A C Supplemental Figure S8 Mino Mino Control ARV-825 Control ARV-771 1.6 -1.6 0.0 88 proteins down 103 proteins down 39 proteins up 56 proteins up C Protein Target Log2 fold change ARV-825/Control P-value Adjusted ARV-771/Control P-Value BRD4 -2.50 2.33E-05 2.22E-05 -3.32 2.48E-08 2.97E-06 p-S6 (S235/236) -2.18 1.27E-06 5.59E-05 -3.16 1.97E-06 2.49E-05 MYC -2.1 4.68E-06 5.82E-05 -1.87 9.03E-05 0.000231 pRb (S807/811) -1.50 5.62E-06 6.33E-05 -2.73 2.93E-08 CIAP2 -0.55 3.47E-06 1.04E-05 5.73E-05 c-RAF -0.53 0.0018 0.003756 -0.81 3.45E-05 0.000113 p-H2AX (S140) 2.32 0.0001 0.000438 2.67 3.42E-07 9.26E-06 Cl Caspase 7 2.54 4.39E-07 2.77 4.62E-07 1E-05 Cl Caspase 3 2.87 1.46E-05 1.14E-04 2.92 1.15E-05 5.84E-05

fold change (OTX015/Control) Supplemental Figure S8 E D Mino Control OTX015 1.6 -1.6 0.0 27 proteins down 10 proteins up F Protein Target Log2 fold change (OTX015/Control) P-value Adjusted P-value p-S6 (S235/236) -2.35 1.27E-06 0.000135 MYC -1.57 6.4E-06 0.000324 pRb (S807/811) -0.76 0.0008 0.007599 CIAP2 -0.34 0.0014 0.0096 Cl Caspase 7 0.79 4.75E-05 0.001666 p-H2AX (S140) 0.99 2.22E-06 0.000169 Cl Caspase 3 1.06 4.93E-05

A B - + - - + - + - + - - + - + - + - + Supplemental Figure S9 Mino Granta-519 MAVER-1 Parental Persister - + - - + - + - + - - + - + - + - + 1000 nM OTX015 500 nM, OTX015, 18 hr 500 nM, ARV-825, 18 hr 200 nM ARV-825 500 nM, ARV-771, 18 hr 200 nM ARV-771 BRD4 c-Myc BRD2 p-BTK c-Myc 1.0 0.98 0.68 0.53 1.0 0.83 0.72 0.54 BTK 1.0 0.41 0.01 0.0 1.05 0.32 0.01 0.0 HEXIM1 XIAP Cyclin D1 BCL-xL 1.0 1.70 0.27 0.0 1.07 1.43 0.14 0.0 CDK4 MCL1 Cyclin D1 XIAP β-Actin 1.0 0.95 0.44 0.20 1.10 0.80 0.32 0.22 cIAP2 1.0 0.69 0.54 0.26 1.07 0.60 0.44 0.29 β-Actin

Supplemental Figure S10 Z138/ GFP-Luc

Supplemental Figure S11 Mino cells Ibrutinib (nM) OTX015 Fraction affected CI Value 1000.0 100.0 0.245 0.72078 2000.0 200.0 0.684 0.26398 4000.0 400.0 0.956 0.07857 6000.0 600.0 0.98 0.06055 8000.0 800.0 0.985 0.06354 10000.0 1000.0 0.974 0.12573 Mino cells Ibrutinib (nM) ARV-771 Fraction affected CI Value 1000.0 10.0 0.644 0.39255 2000.0 20.0 0.931 0.12627 4000.0 40.0 0.956 0.16399 6000.0 60.0 0.966 0.19293 8000.0 80.0 0.97 0.22881 10000.0 100.0 0.977 0.22338 Mino cells venetoclax (nM) OTX015 Fraction affected CI Value 100.0 0.643 0.81389 200.0 0.743 0.97641 400.0 0.972 0.14336 600.0 0.988 0.08977 800.0 0.993 0.06973 1000.0 0.995 0.06253 Mino cells venetoclax (nM) ARV-771 Fraction affected CI Value 100.0 10.0 0.843 0.33535 200.0 20.0 0.865 0.55814 400.0 40.0 0.998 0.01386 600.0 60.0 0.989 0.11334 800.0 80.0 0.99 0.13724 1000.0 100.0 0.995 0.85649 JeKo-1 cells Ibrutinib (nM) OTX015 Fraction affected CI Value 1000.0 100.0 0.075 0.96468 2000.0 200.0 0.136 0.49357 4000.0 400.0 0.394 0.10759 6000.0 600.0 0.288 0.31167 8000.0 800.0 0.296 0.39291 10000.0 1000.0 0.584 0.10106 JeKo-1 cells Ibrutinib (nM) ARV-771 Fraction affected CI Value 500.0 10.0 0.199 0.74494 1000.0 20.0 0.369 0.47286 4000.0 80.0 0.649 0.40890 6000.0 120.0 0.782 0.25483 8000.0 160.0 0.896 0.10661 10000.0 200 0.958 0.03682 JeKo-1 cells venetoclax (nM) OTX015 Fraction affected CI Value 100.0 0.111 0.27842 200.0 0.142 0.26920 400.0 0.24 0.22582 600.0 0.288 0.25269 800.0 0.219 0.52065 1000.0 0.252 0.52278 JeKo-1 cells venetoclax (nM) ARV-771 Fraction affected CI Value 100.0 10.0 0.291 0.36799 200.0 20.0 0.385 0.42170 400.0 40.0 0.572 0.31013 600.0 60.0 0.681 0.25079 800.0 80.0 0.745 0.22106 1000.0 100.0 0.816 0.15933

Supplemental Figure S11 PD CD19+ MCL cells Ibrutinib (nM) OTX015 (nM) Fraction affected CI Value 2000 200 0.454 0.98365 3000 300 0.557 0.27290 4000 400 0.542 0.46597 5000 500 0.558 0.44738 10000 1000 0.638 0.22927 PD CD19+ MCL cells Ibrutinib (nM) ARV-771 Fraction affected CI Value 1000.0 50.0 0.508 0.29147 2000.0 100.0 0.565 0.20738 4000.0 200.0 0.604 0.21789 6000.0 300.0 0.617 0.26712 8000.0 400.0 0.643 0.24262 10000.0 500.0 0.656 0.25270 PD CD19+ MCL cells Venetoclax (nM) OTX015 Fraction affected CI Value 50.0 50.0 0.214 0.69892 100.0 100.0 0.421 0.30533 200.0 200.0 0.462 0.47195 300.0 300.0 0.46 0.71681 400.0 400.0 0.483 0.82842 500.0 500.0 0.499 0.93778 PD CD19+ MCL cells Venetoclax (nM) ARV-771 Fraction affected CI Value 50.0 25.0 0.432 0.09610 100.0 0.441 0.18167 200.0 0.452 0.33926 300.0 150.0 0.511 0.35341 400.0 0.501 0.50118 500.0 250.0 0.533 0.51417 PD CD19+ MCL cells Palbociclib (nM) OTX015 Fraction affected CI Value 500.0 50.0 0.569 0.25123 2000.0 200.0 0.6 0.65460 3000.0 300.0 0.68 0.32300 4000.0 400.0 0.743 0.17484 5000.0 500.0 0.744 0.21537 PD CD19+ MCL cells Palbociclib (nM) ARV-771 Fraction affected CI Value 500.0 50.0 0.621 0.33871 1000.0 100.0 0.678 0.28859 2000.0 200.0 0.663 0.72696 3000.0 300.0 0.751 0.25624 4000.0 400.0 0.702 0.78870 5000.0 500.0 0.736 0.55724

Supplemental Figure S12 Z138 Combination index values Venetoclax Palbociclib

Supplemental Figure S13 Z138 cells Venetoclax nM OTX015 Fraction affected CI Value 100.0 0.201 3.99404 200.0 0.269 0.33093 400.0 0.438 0.01735 600.0 0.296 0.40337 800.0 0.408 0.05444 1000.0 0.330 0.27944 Z138 cells Venetoclax (nM) ARV-771 Fraction affected CI Value 100.0 10.0 0.317 0.43099 200.0 20.0 0.559 0.32293 400.0 40.0 0.681 0.41080 600.0 60.0 0.721 0.52263 800.0 80.0 0.808 0.45804 1000.0 100.0 0.880 0.35519 Z138 cells Palbociclib (nM) OTX015 Fraction affected CI Value 1000.0 100 0.296 0.44721 2000.0 200 0.352 0.50789 4000.0 400 0.356 0.97755 Z138 cells Palbociclib (nM) ARV-771 Fraction affected CI Value 500.0 10.0 0.37 0.31826 1000.0 20.0 0.447 0.47524 2000.0 40.0 0.689 0.39751 3000.0 60.0 0.782 0.39403 4000.0 80.0 0.906 0.22465 5000.0 100.0 0.943 0.17650

Supplemental Figure S13 Mino/Persister cells Venetoclax (nM) OTX015 Fraction affected CI Value 200.0 200.0 0.573 0.44630 400.0 400.0 0.69 0.35245 600.0 600.0 0.677 0.58571 800.0 800.0 0.766 0.38126 1000.0 1000.0 0.776 0.43783 Mino/Persister cells Venetoclax (nM) ARV-771 Fraction affected CI Value 100.0 10.0 0.516 0.55164 200.0 20.0 0.560 0.76371 400.0 40.0 0.632 0.83625 600.0 60.0 0.740 0.47678 800.0 80.0 0.813 0.29277 1000.0 100.0 0.885 0.13325 Mino/Persister cells Palbociclib (nM) OTX015 Fraction affected CI Value 500.0 100.0 0.26 0.90080 1000.0 200.0 0.407 0.72302 2000.0 400.0 0.61 0.48424 3000.0 600.0 0.661 0.54461 4000.0 800.0 0.724 0.49428 5000.0 1000.0 0.732 0.58645 Mino/Persister cells Palbociclib (nM) ARV-771 Fraction affected CI Value 500.0 10.0 0.38 0.99384 3000.0 60.0 0.706 0.60601 4000.0 80.0 0.824 0.26420 5000.0 100.0 0.921 0.07169