Abstract
Aggressive therapy-resistant and refractory acute myeloid leukemia (AML) has an extremely poor outcome. By analyzing a large number of genetically complex and diverse, primary high-risk poor-outcome human AML samples, we identified specific pathways of therapeutic vulnerability. Through drug screens followed by extensive in vivo validation and genomic analyses, we found inhibition of cytosolic and mitochondrial anti-apoptotic proteins XIAP, BCL2 and MCL1, and a key regulator of mitosis, AURKB, as a vulnerability hub based on patient-specific genetic aberrations and transcriptional signatures. Combinatorial therapeutic inhibition of XIAP with an additional patient-specific vulnerability eliminated established AML in vivo in patient-derived xenografts (PDXs) bearing diverse genetic aberrations, with no signs of recurrence during off-treatment follow-up. By integrating genomic profiling and drug-sensitivity testing, this work provides a platform for a precision-medicine approach for treating aggressive AML with high unmet need.
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Data availability
All DNA and RNA sequencing datasets produced in this study were deposited at the National Bioscience Database Center. Accession numbers are hum0116 for DNA sequencing data and hum0243 for RNA-seq data. Differential expression analysis results can be browsed interactively on ZENBU at https://fantom.gsc.riken.jp/zenbu/reports/#Identification_of_therapeutic_targets_in_poor_outcome_AML_patients. Any other relevant data are available from the corresponding author upon reasonable request. Source data are provided with this paper.
Code availability
The scripts for motif activity analysis are available at http://fantom.gsc.riken.jp/5/suppl/Alam_et_al_2020/34.
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Acknowledgements
F.I. is supported by the RIKEN President’s Discretionary Fund. Support from colleagues at Toranomon Hospital is gratefully acknowledged.
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Conceptualization, M.H., Y.S. and F.I.; methodology, M.H., M.Y., M.d.H. and Y.M.; formal analysis, M.H., M.Y., S. Takata, M.E., H.A., T.W., J.A.R., J.S., A.K., H.Y. and Y.S.; investigation, M.H., R.N., I.O., A.K., K.S., H.K., S.F., R.-i.M., K.O. and Y.S.; resources, N.U., S. Takagi and S. Taniguchi; writing (original draft), M.H. and Y.S.; writing (review and editing), Y.S., T.F., Y.O., T.H., O.O., L.D.S., P.V., M.d.H., Y.M. and F.I.; supervision, Y.S., O.O., L.D.S., P.V., M.d.H., Y.M. and F.I.; funding acquisition, F.I.
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Peer review information Nature Cancer thanks Marina Konopleva and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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Extended data
Extended Data Fig. 1 Target identification and chemical screening to discover vulnerabilities in poor prognosis AML.
a, Distribution of risk groups in present study cohort (n = 216 AML patients) compared with previously published AML studies16,17,18. b,c, RNAseq results of (b) FLT3 WT and (c) FLT3-mutated AML-engrafting cells obtained from deceased patients (n = 86; FLT3 WT n = 54, FLT3-mutated n = 32) was compared with normal CD34 + hematopoietic stem/progenitor cells obtained from healthy donors (n = 44) and illustrated in a volcano plot showing Log2FC and Benjamini-Hochberg adjusted p-value (-log base10). Genes targeted by inhibitors were highlighted by red color. d, Representative in vitro 35-compound chemical screening in a 96-well format. Equal numbers of AML cells were exposed to test compounds at concentrations of 30 nM and 300 nM. Note a dose-dependent reduction in AML cell cluster size with AZD5582, YM155, venetoclax, S63845, dinaciclib, GSK923295, SB74391 and barasertib compared to vehicle controls. e, CB HSPCs were exposed to each compound for 72 hours at doses indicated (YM155: 100 nM n = 2, 300 nM n = 2; dinaciclib: 30 nM n = 3, 100 nM n = 3; SB743921: 30 nM n = 3, 100 nM n = 2; AZD5582: 1 nM n = 6, 3 nM n = 6, 10 nM n = 6, 30 nM n = 7; venetoclax: 100 nM n = 2, 300 nM n = 3; S63845: 100 nM n = 3, 300 nM n = 3; barasertib: 30 nM n = 3, 100 nM n = 4; GSK923295: 30 nM n = 3, 100 nM n = 3; n represents number of CB samples). For each compound, the concentration achieving effective in vitro AML elimination as shown in Fig. 2a is indicated by red color. Data are shown as mean + /-s.e.m. f, AZD5582 selectively targeted human AML cells compared with CB-derived HSPCs in vitro (n = 20, 20, 19 AML cases at 3, 10, 30 nM respectively; CB HSPCs n = 5 at each dose; p = 9.71e-12, 1.67e-11, 9.97e-9, respectively for comparison between AML and CB HSCPs at each dose by unpaired two-tailed t-test; mean + /-s.e.m.). g, Viability, proliferation and differentiation capacity of CB-derived CD34 + HSPCs exposed to 30 nM AZD5582 were assessed using single-cell colony-forming cell (CFC) assay. Numbers of erythroid (BFU-E) and myeloid (CFU-M, CFU-GM) colonies arising from single AZD5582-treated CB HSPCs were compared with vehicle treated CB HSPCs and tested by paired two-tailed t-test. Three independent experiments were performed and data presented as mean + /-s.e.m. h, Viability of 15 patient samples containing both AML cells and T cells treated with AZD5582 at 30 nM were compared with those treated with vehicle control in vitro at 30 nM. Representative flow cytometry dot plot showing effective elimination of leukemia cells and sparing of human T cells by AZD5582 (Patient 74).
Extended Data Fig. 2 Heterogeneous responses of AML cells to compounds including a SMAC-mimetic/IAP inhibitor AZD5582.
a, Targeting BIRC4 and BIRC2 through transduction of ribonucleotide complex consisting of Cas9 protein and guide RNA targeting BIRC2 and BIRC4 was performed in AZD5582-sensitive Molm13 cells and AZD5582-resistant TF1a cells. Mean with sem of three independent experiments are shown. Significant differences were detected using unpaired two-tailed t-test. b, Viability of FLT3 WT AML treated with AZD5582 were compared with monovalent SMAC-mimetic AT406 and second-generation SMAC-mimetic/bivalent antagonist of IAP proteins birinapant. AZD5582 3 nM n = 7, 30 nM n = 15; birinapant 3 nM n = 3, 30 nM n = 9; AT406 3 nM n = 3, 30 nM n = 9; p = 0.000116 and 0.000307 for comparison of each compound against AZD5582 at 3 nM, p = 2.26e-13 and 4.74e-5 for each comparison at 30 nM by unpaired two-tailed t-test where n represents the number of AML cases. Data are presented as mean + /-s.e.m. c, In vitro responses to AZD5582, birinapant, venetoclax, S63845, barasertib and GSK923295 are shown for human AML cells obtained from PDX mice (n = 21). d, Correlation between Responsiveness profiles of AZD5582 at 30 nM and birinapant at 300 nM against 21 human AML samples was analyzed by Pearson’s correlation test (r = 0.9864, two-tailed p-value=2.32e-16).
Extended Data Fig. 3 In vitro responsiveness of leukemia cells to five compounds in order of elimination efficacy of S63845, barasertib and GSK923295.
AML cases are arranged in the order of responsiveness to a, S63845, b, barasertib and c, GSK923295. Information on selected somatic mutations and chromosome abnormalities are shown below (n = 66).
Extended Data Fig. 4 XIAP dependence in TP53-mutated human AML cells correlates with TP53-regulated transcription of BBC3.
a,e, The regions of (a) chromosome 19 containing BBC3 gene, structure of BBC3 gene and its transcripts and (e) chromosome 15 containing AEN gene, structure of AEN gene and its transcripts obtained from FANTOM5 database. b,f, In AML cells, (b) a major BBC3 transcription start site (TSS) associated with ENST00000439096.2 and f, AEN TSS associated with ENST00000332810.3, ENST00000557787.1, ENST00000559528.1, ENST00000560174.1 and ENST00000558327.1 were identified through CAGE-sequencing. Correlation of AZD5582 responsiveness with promoter activity upstream of the identified TSS for b, BBC3 and f, AEN. AZD5582-sensitive n = 25, AZD5582-resistant n = 2 (TP53 mutations Glu286Val, Ile255del and Val73fs). c,g, Previously reported ChIP-seq data in two leukemia cell lines K562 and Molm13 confirming binding of WT TP53 and TP53 mutants Tyr220Cys and Arg282Trp with preserved TP53 motif activity to the promoter region upstream of the identified TSS for c, BBC3 and g, AEN. Promoter binding was abolished in TP53 KO cells. d,h, ChIP-seq data obtained from ENCODE confirming specificity of TP53 binding to d, BBC3 promoter and h, AEN promoter as compared with non-specific binding pattern for all human transcription factors.
Extended Data Fig. 5 In vivo efficacy of AZD5582-based combination treatments.
a, Frequencies of human CD45+ AML cells in the recipient spleen with or without treatment are shown. For each category, 91 PDX mice created from 8 AML cases with sensitivity to both AZD5582 and venetoclax, 33 PDX mice created from 4 AML cases with sensitivity to AZD5582 but resistance to venetoclax and 15 PDX mice created from 2 AML cases with resistance to AZD5582 but sensitivity to venetoclax were analyzed. Data are shown as mean + /-s.e.m. Detailed data for each PDX-model mouse is summarized in Supplementary Table 8. b.c, AML cell elimination in (b) femurs and (c) spleens of PDX mice, shown by immunohistochemical staining for human CD45+ (brown) and HE staining. Broken lines indicate blood vessels containing erythrocytes; arrowheads indicate neutrophils; arrows indicate megakaryocytes.
Extended Data Fig. 6 Recovery of normal hematopoiesis in mice treated with AZD5582-based combination treatments.
a, Human CD45-labeled and HE-stained femoral sections and b, PB flow cytometry of Patient 9, 1, 22, 2 and 51 PDX mice during 4-week course of AZD5582 and AZD5582-based combination treatments. In (a), white broken lines in HE-stained images outline blood vessels containing erythrocytes and arrows indicate murine megakaryocytes. Femoral section and PB flow cytometry from a non-recipient NSG mice are shown as comparison. c, Following in vivo treatment with AZD5582 combined with venetoclax and AZD5582 combined with barasertib, Mac1+ Gr1- monocytes and Mac1+ Gr1+ granulocytes were found in the recipient BM (representative flow cytometry plots shown). Mac1+ Gr1- monocytes and Mac1+ Gr1+ granulocytes were identified by May-Grunwald Giemsa staining after treatment with AZD5582 and venetoclax.
Extended Data Fig. 7 Individualized patient response to in vivo therapeutic targeting of XIAP, BCL2 and MCL1.
a,b, Individualized patient response to AZD5582-based combination therapy with (a) venetoclax and (b) S63845 are shown. Number of PDX models generated for each patient are presented above the panels. Significance of AML cell elimination was assessed by paired two-tailed t-test (PB) and unpaired two-tailed t-test (BM, SPL). PB, peripheral blood; BM, bone marrow; SPL, spleen; Pre, pre-treatment; Post, post-treatment.
Extended Data Fig. 8 Individualized patient response to in vivo therapeutic targeting of XIAP, AURKB and KIF10.
a,b, Individualized patient response to AZD5582-based combination therapy with (a) barasertib and (b) GSK923295 are shown. Number of PDX models generated for each patient are presented above the panels. Significance of AML cell elimination was assessed by paired two-tailed t-test (PB) and unpaired two-tailed t-test (BM, SPL). PB, peripheral blood; BM, bone marrow; SPL, spleen; Pre, pre-treatment; Post, post-treatment.
Extended Data Fig. 9 No sign of recurrence at four weeks off-treatment following a four-week course of AZD5582/venetoclax combination.
a,b, Human CD45-labeled and HE-stained thin sections of femurs from (a) untreated and (b) AZD5582/venetoclax combination-treated Patient 2 PDX mice. White broken lines in HE-stained images outline blood vessels containing erythrocytes. Arrows indicate hCD45-negative murine megakaryocytes. c, Thin sections of femurs from untreated and AZD5582/venetoclax treated PDX-model mice for five AML patients are shown as indicated. The sections were labeled with human CD45 (three panels on the left for each patient) or with HE (two panels on the right for each patient). AZD5582/venetoclax treated mice were first engrafted with patient-derived AML cells then underwent a four-week course of treatment followed by over four weeks off-treatment. The lengths of the scale bars are indicated in panels for Patient 9.
Extended Data Fig. 10 Genetic alterations and treatment response in poor prognosis AML.
a, Response to venetoclax treatment in AML cells with normal chromosome 7 (82 AML cases) and monosomy 7 (21 AML cases). A two-tailed t-test was used to determine statistical significance. b, Correlation between TP53 motif activity and AZD5582 sensitivity in TP53-mutated AML cells with normal chromosome 3, no MLL-rearrangement and wild type IDH1, IDH2, TET2, CBL and NRAS genes (n = 19 AML cases, Pearson’s correlation r = 0.6174, two-tailed p-value=0.0049). c, Correlation between genetic alterations and dependence on XIAP and BCL2 for survival in high-risk AML. Pink arrows, greater dependence on XIAP; blue arrows, greater dependence on BCL2; black arrows, both XIAP- and BCL2-independent. Cases in the pink box are responsive to AZD5582 only or responsive to both AZD5582 and venetoclax in vitro with greater responsiveness to AZD5582; cases in the blue box are responsive to venetoclax only or responsive to both AZD5582 and venetoclax in vitro with greater responsiveness to venetoclax; cases in the black box are responsive to neither in vitro.
Supplementary information
Supplementary Information
Supplementary Figs. 1 and 2.
Supplementary Tables
Supplementary Tables 1–12
Supplementary Video 1
Location of mutated amino acid residues and altered sensitivity to AZD5582. The three-dimensional coordinates of the complex of p53 protein and DNA were obtained from Protein Data Bank (PDB ID 2AHI). p53 protein and DNA backbones are represented with gray and green ribbons, respectively. The zinc ion is shown as a cyan sphere. Mutated amino acid residues are shown as ball-and-stick representations in blue to red, based on AZD5582 elimination (red, sensitive; blue, resistant). These figures were drawn by MOE 2019.0102 (refs. 59,60).
Supplementary Video 2
Location of mutated amino acid residues and altered motif activity of TP53. The three-dimensional coordinates of the complex of p53 protein and DNA were obtained from Protein Data Bank (PDB ID 2AHI). p53 protein and DNA backbones are represented with gray and green ribbons, respectively. The zinc ion is shown as a cyan sphere. Mutated amino acid residues are shown as ball-and-stick representations in blue to red, based on TP53 motif activity values (red, high motif activity; blue, low motif activity). These figures were drawn by MOE 2019.0102 (refs. 59,60).
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Hashimoto, M., Saito, Y., Nakagawa, R. et al. Combined inhibition of XIAP and BCL2 drives maximal therapeutic efficacy in genetically diverse aggressive acute myeloid leukemia. Nat Cancer 2, 340–356 (2021). https://doi.org/10.1038/s43018-021-00177-w
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DOI: https://doi.org/10.1038/s43018-021-00177-w
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