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

PublishRudolph Dawson Modified over 5 years ago

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Presentation on theme: "Supplemental Figure S1. Gene Granta-519 MAVER-1 JeKo-1 Mino Z-138 ATM"— Presentation transcript:

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

2 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

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

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

5 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

6 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

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

8 Supplemental Figure S5 A B † † † * * *

9 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

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

11 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

12 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 E-05 -2.81 3.933E-07 E-05 BCL2 -0.32 -0.48 BCL2L1 -1.47 -1.18 BTK -0.35 -0.47 PRDM1 -2.44 2.807E-05 -1.42 TNFAIP3 1.53 5.262E-05 0.69 PMAIP1 1.15 0.62 HEXIM1 2.16 1.817E-07 E-05 2.36 2.756E-07 E-05 CDKN1A 0.95 0.72 Remove BMI

13 Remove transcription box totally
Supplemental Table S6 GSEA with REACTOME pathways ARV-825 OTX015 REACTOME_SIGNALING_BY_THE_B_CELL_RECEPTOR_BCR REACTOME_GPCR_DOWNSTREAM_SIGNALING REACTOME_SIGNALING_BY_GPCR REACTOME_SIGNALING_BY_EGFR_IN_CANCER REACTOME_SIGNALING_BY_FGFR REACTOME_DOWNSTREAM_SIGNAL_TRANSDUCTION REACTOME_PI_3K_CASCADE REACTOME_PI3K_AKT_ACTIVATION REACTOME_METABOLISM_OF_AMINO_ACIDS_AND_DERIVATIVES REACTOME_RESPIRATORY_ELECTRON_TRANSPORT REACTOME_CHROMOSOME_MAINTENANCE REACTOME_TELOMERE_MAINTENANCE REACTOME_DNA_REPAIR REACTOME_CELL_CYCLE REACTOME_CELL_CYCLE_MITOTIC REACTOME_CELL_CYCLE_CHECKPOINTS REACTOME_G1_S_TRANSITION Cell Signaling/ Signal Transduction Metabolism/ electron transport Chromatin Cell Cycle Remove transcription box totally

14 Supplemental Table S7 Transcription/ Translation Metabolism/
GSEA with REACTOME pathways ARV-825 OTX015 REACTOME_METABOLISM_OF_RNA REACTOME_METABOLISM_OF_MRNA REACTOME_TRANSLATION REACTOME_PROCESSING_OF_CAPPED_INTRON_CONTAINING_PRE_MRNA REACTOME_MITOCHONDRIAL_PROTEIN_IMPORT REACTOME_MRNA_PROCESSING REACTOME_MRNA_SPLICING REACTOME_RNA_POL_III_TRANSCRIPTION REACTOME_RNA_POL_III_TRANSCRIPTION_INITIATION_FROM_TYPE_2_PROMOTER REACTOME_TRANSPORT_OF_MATURE_TRANSCRIPT_TO_CYTOPLASM REACTOME_CLEAVAGE_OF_GROWING_TRANSCRIPT_IN_THE_TERMINATION_REGION REACTOME_RNA_POL_III_TRANSCRIPTION_TERMINATION REACTOME_DEADENYLATION_DEPENDENT_MRNA_DECAY REACTOME_METABOLISM_OF_NON_CODING_RNA REACTOME_APC_C_CDH1_MEDIATED_DEGRADATION_OF_CDC20_AND_OTHER_APC_C_CDH1_TARGETED_PROTEINS_IN_LATE_MITOSIS_EARLY_G1 REACTOME_TRANSPORT_OF_GLUCOSE_AND_OTHER_SUGARS_BILE_SALTS_AND_ORGANIC_ACIDS_METAL_IONS_AND_AMINE_COMPOUNDS REACTOME_APC_C_CDC20_MEDIATED_DEGRADATION_OF_MITOTIC_PROTEINS REACTOME_PURINE_RIBONUCLEOSIDE_MONOPHOSPHATE_BIOSYNTHESIS REACTOME_METABOLISM_OF_PROTEINS REACTOME_SLC_MEDIATED_TRANSMEMBRANE_TRANSPORT REACTOME_GLUCURONIDATION Transcription/ Translation Metabolism/ electron transport

15 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 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 -0.81 3.45E-05 p-H2AX (S140) 2.32 0.0001 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

16 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 MYC -1.57 6.4E-06 pRb (S807/811) -0.76 0.0008 CIAP2 -0.34 0.0014 0.0096 Cl Caspase 7 0.79 4.75E-05 p-H2AX (S140) 0.99 2.22E-06 Cl Caspase 3 1.06 4.93E-05

17 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 BTK HEXIM1 XIAP Cyclin D1 BCL-xL CDK4 MCL1 Cyclin D1 XIAP β-Actin cIAP2 β-Actin

18 Supplemental Figure S10 Z138/ GFP-Luc

19 Supplemental Figure S11 Mino cells Ibrutinib (nM) OTX015
Fraction affected CI Value      100.0 0.245           200.0 0.684           400.0 0.956           600.0 0.98           800.0 0.985         1000.0 0.974      Mino cells Ibrutinib (nM) ARV-771 Fraction affected CI Value     10.0 0.644          20.0 0.931          40.0 0.956          60.0 0.966          80.0 0.97         100.0 0.977      Mino cells venetoclax (nM) OTX015 Fraction affected CI Value 100.0 0.643     200.0 0.743     400.0 0.972     600.0 0.988     800.0 0.993     1000.0 0.995     Mino cells venetoclax (nM) ARV-771 Fraction affected CI Value 100.0      10.0 0.843      200.0      20.0 0.865      400.0      40.0 0.998      600.0      60.0 0.989      800.0      80.0 0.99      1000.0    100.0 0.995      JeKo-1 cells Ibrutinib (nM) OTX015 Fraction affected CI Value    100.0 0.075    200.0 0.136      400.0 0.394     600.0 0.288     800.0 0.296     1000.0 0.584 JeKo-1 cells Ibrutinib (nM) ARV-771 Fraction affected CI Value 500.0 10.0 0.199 1000.0 20.0 0.369 4000.0 80.0 0.649 6000.0 120.0 0.782 8000.0 160.0 0.896   200 0.958 JeKo-1 cells venetoclax (nM) OTX015 Fraction affected CI Value 100.0 0.111      200.0 0.142      400.0 0.24      600.0 0.288      800.0 0.219      1000.0 0.252      JeKo-1 cells venetoclax (nM) ARV-771 Fraction affected CI Value 100.0      10.0 0.291      200.0      20.0 0.385      400.0      40.0 0.572      600.0      60.0 0.681      800.0      80.0 0.745      1000.0    100.0 0.816     

20 Supplemental Figure S11 PD CD19+ MCL cells Ibrutinib (nM) OTX015 (nM)
Fraction affected CI Value 2000 200  0.454      3000 300 0.557      4000 400 0.542      5000 500 0.558      10000 1000 0.638      PD CD19+ MCL cells Ibrutinib (nM) ARV-771 Fraction affected CI Value      50.0 0.508           100.0 0.565           200.0 0.604           300.0 0.617           400.0 0.643           500.0 0.656      PD CD19+ MCL cells Venetoclax (nM) OTX015 Fraction affected CI Value 50.0      50.0   0.214 100.0      100.0    0.421  200.0      200.0    0.462 300.0      300.0    0.46   400.0      400.0    0.483 500.0      500.0    0.499  PD CD19+ MCL cells Venetoclax (nM) ARV-771 Fraction affected CI Value 50.0      25.0      0.432  100.0      0.441 200.0      0.452 300.0      150.0      0.511 400.0      0.501 500.0      250.0      0.533 PD CD19+ MCL cells Palbociclib (nM) OTX015 Fraction affected CI Value 500.0      50.0 0.569           200.0 0.6           300.0 0.68           400.0 0.743           500.0 0.744      PD CD19+ MCL cells Palbociclib (nM) ARV-771 Fraction affected CI Value 500.0      50.0 0.621           100.0 0.678           200.0 0.663           300.0 0.751           400.0 0.702           500.0 0.736     

21 Supplemental Figure S12 Z138 Combination index values Venetoclax
Palbociclib

22 Supplemental Figure S13 Z138 cells Venetoclax nM OTX015
Fraction affected CI Value 100.0 0.201 200.0 0.269 400.0 0.438 600.0 0.296 800.0 0.408 1000.0 0.330 Z138 cells Venetoclax (nM) ARV-771 Fraction affected CI Value 100.0      10.0 0.317      200.0      20.0 0.559      400.0      40.0 0.681      600.0      60.0 0.721      800.0      80.0 0.808           100.0 0.880     Z138 cells Palbociclib (nM) OTX015 Fraction affected CI Value      100 0.296           200 0.352           400 0.356      Z138 cells Palbociclib (nM) ARV-771 Fraction affected CI Value 500.0 10.0      0.37      1000.0 20.0      0.447      2000.0 40.0      0.689      3000.0 60.0      0.782      4000.0 80.0      0.906      5000.0 100.0     0.943     

23 Supplemental Figure S13 Mino/Persister cells Venetoclax (nM) OTX015
Fraction affected CI Value 200.0      200.0     0.573      400.0      400.0     0.69      600.0      600.0     0.677      800.0      800.0     0.766             0.776      Mino/Persister cells Venetoclax (nM) ARV-771 Fraction affected CI Value 100.0      10.0 0.516     200.0      20.0 0.560    400.0      40.0 0.632    600.0      60.0 0.740     800.0      80.0 0.813       100.0 0.885     Mino/Persister cells Palbociclib (nM) OTX015 Fraction affected CI Value 500.0 100.0      0.26      1000.0 200.0      0.407      2000.0 400.0      0.61      3000.0 600.0      0.661      4000.0 800.0      0.724      5000.0    0.732      Mino/Persister cells Palbociclib (nM) ARV-771 Fraction affected CI Value 500.0 10.0      0.38      3000.0 60.0      0.706      4000.0 80.0      0.824      5000.0 100.0      0.921     

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