Supplemental Figure S1 B A C D.

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Supplemental Material

Whole cell lysates from mice

Presentation transcript:

Supplemental Figure S1 B A C D

* * ** ** A B HEL92.1.7 SET2 Supplemental Figure S2 IgG isotype control Control 500 1000 nM JQ1, 24 h 0.8% 40.4% 12.3% 9.9% HEL92.1.7 Cell counts (FL-2) IL7R (FL-2) IL7R (FL-2) IL7R (FL-2) 1.0% 3.5% 2.2% 1.7% Cell counts SET2 (FL-2) IL7R (FL-2) IL7R (FL-2) IL7R (FL-2) B * * ** **

B A C MV4-11 p-STAT5 STAT5 c-Myc CDK6 CDK4 HEXIM1 p21 BIMEL BIML BIMs Supplemental Figure S3 B A MV4-11 0 250 1000 nM, OTX-015, 24 hr p-STAT5 STAT5 c-Myc CDK6 CDK4 HEXIM1 p21 C BIMEL BIML BIMs β-Actin

Supplemental Figure S4 A *** = p< 0.005 B *** ***

A B SET2 downregulated 37 proteins upregulated 8 proteins SET2 Supplemental Figure S5 A SET2 Control 1 µM ruxolitinib 1 2 3 1 2 3 Protein Target Log2 fold change (ruxolitinib/Control) P-value pS6 (S235/236) -2.89 1.23E-06 pSTAT3 (Y705) -1.96 8.28E-06 p4E-BP1(T37/46) -0.68 1.14E-05 pPRAS40 (T246) -0.55 0.00014 p4E-BP1 (S65) -0.53 0.0035 Beta Catenin -0.33 0.0068 Cl Caspase 7 1.14 7.26E-08 Cl Caspase 3 1.26 8.13E-07 H2AX pS140 1.79 4.04E-05 -1.6 1.6 0.0 downregulated 37 proteins upregulated 8 proteins SET2 B Control 1 µM pacritinib Protein Target Log2 fold change (pacritinib/Control) P-value pS6 (S235/236) -2.1 2.81E-06 pSTAT3 (Y705) -0.81 0.0019 pPRAS40 (T246) -0.67 5.38E-05 p4E-BP1 pS65 -0.60 0.0016 p4E-BP1(T37/46) -0.52 0.0015 pAKT (S473) -0.38 0.0409 Cl Caspase 7 1.18 0.0003 Cl Caspase 3 1.29 8.66E-06 H2AX pS140 1.45 0.0001 1 2 3 1 2 3 -1.6 1.6 0.0 downregulated 28 proteins upregulated 14 proteins

C A B D SET2 + 0.5 µM Rux p-STAT5 STAT5 p-STAT3 STAT3 c-MYC 2.0 SET2 Supplemental Figure S6 A C SET2 HEL92.1.7 cells JQ1 (nM) ruxolitinib (nM) Fa CI Value 250 500 0.6806 0.153 300 600 0.7003 0.163 350 700 0.7259 400 800 0.6949 0.225 1000 0.722 0.238 + 0.5 µM Rux 0 0.25 1.0 0 0.25 1.0 µM, JQ1, 24 h p-STAT5 STAT5 p-STAT3 STAT3 B c-MYC SET2 JQ1 and ruxolitinib Combination Index Fractional effect 2.0 1.0 0.5 0.0 PIM1 p21 β-Actin D SET2 OTX-015 and ruxolitinib Combination Index Fractional effect 2.0 1.0 0.5 0.0 OTX-015 (nM) ruxolitinib (nM) Fa CI Value 125 250 0.876 0.4939 150 300 0.912 0.4603 175 350 0.934 0.4379 187.5 375 0.922 0.5278 200 400 0.898 0.6833 225 450 0.946 0.4899 500 0.966 0.3980 JQ1 (nM) ruxolitinib (nM) Fa CI Value 200 0.604 0.21826 250 0.639 0.22694 300 0.668 0.23346 350 0.774 0.14877 400 0.804 0.13976 500 0.21253

E G F HEL92.1.7 2.0 2.0 HEL92.1.7 SET2 JQ1 and pacritinib Supplemental Figure S6 HEL92.1.7 JQ1 and pacritinib Fractional effect 2.0 1.0 0.5 0.0 Combination Index E F G HEL92.1.7 0 0.25 1.0 0 0.25 1.0 µM JQ1, 24 h +1 µM pacritinib p-STAT5 p-STAT3 STAT5 STAT3 BCL-2 Bcl-xL c-MYC CDK4 CDK6 Cl PARP PIM1 β-Actin Combination Index Fractional effect 2.0 1.0 0.5 0.0 SET2 JQ1 and pacritinib HEL92.1.7 cells JQ1 (nM) pacritinib (nM) Fa CI Value 500 0.541 0.4558 600 0.378 0.8943 700 0.442 0.8571 900 0.523 0.8657 1000 0.616 7.25E-4 SET2 cells JQ1 (nM) pacritinib (nM) Fa CI Value 200 0.505 0.2051 250 0.579 0.1495 300 0.650 0.1072 350 0.702 0.0847 400 0.810 0.0389 500 0.756 0.0786

H I HEL92.1.7 SET2 JQ1 + SAR302503 JQ1 + SAR302503 Combination index Supplemental Figure S6 H I SET2 JQ1 + SAR302503 0.5 1.0 1.5 2.0 Fractional effect Combination index 0.2 0.4 0.6 0.8 1.0 0.5 1.5 Fractional Effect CI HEL92.1.7 JQ1 + SAR302503 HEL92.1.7 JQ1 (nM) SAR302503 Fa CI Value 250 500 0.3959 0.823 300 600 0.4674 0.732 350 700 0.5491 0.637 400 800 0.6075 0.602 1000 0.6768 0.608 SET2 JQ1 (nM) SAR302503 Fa CI Value 125 500 0.820 0.6777 150 600 0.885 0.5813 175 700 0.863 0.7709 187.5 750 0.920 0.5625 200 800 0.893 0.7360 225 900 0.902 0.7779

Supplemental Figure S7 % of Pts With mutation Patient # 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 BCR/ABL ABL1 ASXL1 DNMT3 EZH2 FLT3 GATA1 HRAS IDH1 IDH2 IKZF2 JAK2 KIT KRAS MLL MPL NOTCH1 NRAS PTPN11 RUNX1 TET2 TP53 WT1 NPM1 BRAF MYD88 CALR CEBPA 30.4 8.7 13 4.3 13 4.3 65.2 4.3 17.4 4.3 13 ASXL1 (blue) JAK2 (Green) TET2 (RED) RUNX1 (Purple) KRAS (Orange) CALR (light green) 17.4 26.1 4.3 4.3

C A D B F E 2.0 PD CD34+ sAML JQ1 and pacritinib 1.0 0.5 0.0 2.0 Supplemental Figure S8 C PD CD34+ sAML JQ1 and pacritinib Fractional effect Combination Index 2.0 1.0 0.5 0.0 A PD CD34+ sAML-1 JQ1 (nM) ruxolitinib FractionalEffect CI 500.0 500.0 0.329 0.24729 1000.0 500.0 0.382 0.23628 2000.0 0.398 0.38133 500.0 1000.0 0.362 0.15523 1000.0 0.395 0.19844 0.436 0.23158 2.0 1.0 0.5 0.0 Combination Index Fractional effect PD CD34+ sAML JQ1 and pacritinib Synergy D B PD CD34+ sAML-2 JQ1 (nM) ruxolitinib (nM) Fractional Effect CI 500.0 0.782 0.0237 1000.0 0.912 0.00211 0.9335 0.952 9.59 E-4 F PD CD34+ sAML JQ1 (nM) pacritinib Fractional Effect CI 400 200 0.347 0.1705 500 250 0.348 0.2112 600 300 0.331 0.2949 700 350 0.317 0.3911 800 400 0.389 0.2382 900 450 0.432 0.1889 E PD CD34+ sAML JQ1 (nM) pacritinib (nM) Fractional Effect CI 500.0 0.691 0.3293 1000.0 0.8905 0.1767 2000.0 0.6735 0.6144 0.895 0.1758

AKT p-AKT p-ERK Mcl-1 p-S6 BCL-2 Bcl-xL Supplemental Figure S9 JQ1 Rux 2.0 2 3 4 5 6 7 1.0 8 9 10 11 12 13 0.5 JQ1 Rux SAR JQ1 Rux SAR JQ1 Rux SAR JQ1 Rux SAR JQ1 Rux SAR BCL-2 Bcl-xL 1 2.0 2 3 4 5 6 7 1.0 8 9 10 11 12 13 0.5 JQ1 Rux SAR JQ1 Rux SAR

A B C E D Panel C will lose HEL cells HEL/JIR + 20 nM AUY922 0 250 1000 0 250 1000 nM, JQ1, 24 h HEL/JIR JQ1 (nM) AUY922 Fa CI Value 500 2.5 0.637 0.62348 600 3.0 0.749 0.52869 700 3.5 0.826 0.48278 800 4.0 0.845 0.51692 900 4.5 0.62072 1000 5.0 0.835 0.66896 p-STAT5 STAT5 STAT3 Panel C will lose HEL cells c-Myc PIM1 CDK6 CDK4 Bcl-xL hsp70 Supplemental Figure S10 β-Actin

* * B A - + - - + - + - + - - + - + C Supplemental Figure S11 HEL92.1.7 Parental Persister - + - - + - + - + - - + - + 500 nM ruxolitinib 500 nM JQ1 * * 500 nM AUY922 p-STAT5 1.0 0.49 0.44 0.01 1.0 0.81 0.43 0.01 STAT5 c-Myc C 1.0 0.81 0.70 0.12 1.0 0.76 0.56 0.08 HEL/Persisters 24 hr JQ1 (nM) AUY922 (nM) Fa CI Value 100 20 0.567 0.35056 125 25 0.522 0.53768 150 30 0.616 0.41968 175 35 0.662 0.39317 200 40 0.700 0.37117 225 45 0.728 0.35972 250 50 0.764 0.32524 PIM1 1.0 0.36 0.05 0.07 1.0 0.38 0.04 0.03 Bcl-xL 1.0 0.54 0.59 0.85 1.0 0.77 0.51 0.76 MCL1 1.0 1.07 0.39 0.40 1.0 0.67 0.54 0.24 β-Actin