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Article: Immune cell proportions correlate with clinicogenomic features and

Romine, Kyle A / Bottomly, Daniel / Yashar, William / Long, Nicola / Viehdorfer, Matthew / McWeeney, Shannon K / Tyner, Jeffrey W

Frontiers in oncology

2023 Volume 13, Page(s) 1192829

Abstract: Introduction: The implementation of small-molecule and immunotherapies in acute myeloid leukemia (AML) has been challenging due to genetic and epigenetic variability amongst patients. There are many potential mechanisms by which immune cells could ... ...

Abstract	Introduction: The implementation of small-molecule and immunotherapies in acute myeloid leukemia (AML) has been challenging due to genetic and epigenetic variability amongst patients. There are many potential mechanisms by which immune cells could influence small-molecule or immunotherapy responses, yet, this area remains understudied. Methods: Here we performed cell type enrichment analysis from over 560 AML patient bone marrow and peripheral blood samples from the Beat AML dataset to describe the functional immune landscape of AML. Results: We identify multiple cell types that significantly correlate with AML clinical and genetic features, and we also observe significant correlations of immune cell proportions with Discussion: Our work, which is accessible through a new "Cell Type" module in our visualization platform (Vizome; http://vizome.org/), can be leveraged to investigate potential contributions of different immune cells on many facets of the biology of AML.
Language	English
Publishing date	2023-06-08
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2649216-7
ISSN	2234-943X
ISSN	2234-943X
DOI	10.3389/fonc.2023.1192829
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Article ; Online: Genome-wide CRISPR screen identifies regulators of MAPK and MTOR pathways mediating sorafenib resistance in acute myeloid leukemia.

Damnernsawad, Alisa / Bottomly, Daniel / Kurtz, Stephen E / Eide, Christopher A / McWeeney, Shannon K / Tyner, Jeffrey W / Nechiporuk, Tamilla

Haematologica

2022 Volume 107, Issue 1, Page(s) 77–85

Abstract: Drug resistance impedes the long-term effect of targeted therapies in acute myeloid leukemia (AML), necessitating the identification of mechanisms underlying resistance. Approximately 25% of AML patients carry FLT3 mutations and develop post-treatment ... ...

Abstract	Drug resistance impedes the long-term effect of targeted therapies in acute myeloid leukemia (AML), necessitating the identification of mechanisms underlying resistance. Approximately 25% of AML patients carry FLT3 mutations and develop post-treatment insensitivity to FLT3 inhibitors, including sorafenib. Using a genome-wide CRISPR screen, we identified LZTR1, NF1, TSC1 or TSC2, negative regulators of the MAPK and MTOR pathways, as mediators of sorafenib resistance. Analyses of ex vivo drug sensitivity assays in FLT3-ITD AML patient samples revealed lower expression of LZTR1, NF1, and TSC2 correlated with sorafenib sensitivity. Importantly, MAPK and/or MTOR complex1 (MTORC1) activity were upregulated in AML cells made resistant to several FLT3 inhibitors, including crenolanib, quizartinib, or sorafenib. These cells were sensitive to MEK inhibitors, and the combination of FLT3 and MEK inhibitors showed enhanced efficacy, suggesting its effectiveness in AML patients with FLT3 mutations and those with resistance to FLT3 inhibitors.
MeSH term(s)	Antineoplastic Agents/pharmacology ; Antineoplastic Agents/therapeutic use ; Cell Line, Tumor ; Clustered Regularly Interspaced Short Palindromic Repeats ; Humans ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/genetics ; MAP Kinase Signaling System ; Mutation ; Niacinamide/pharmacology ; Niacinamide/therapeutic use ; Phenylurea Compounds/pharmacology ; Phenylurea Compounds/therapeutic use ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Sorafenib/pharmacology ; TOR Serine-Threonine Kinases/genetics ; Transcription Factors ; fms-Like Tyrosine Kinase 3/genetics
Chemical Substances	Antineoplastic Agents ; LZTR1 protein, human ; Phenylurea Compounds ; Protein Kinase Inhibitors ; Transcription Factors ; Niacinamide (25X51I8RD4) ; Sorafenib (9ZOQ3TZI87) ; MTOR protein, human (EC 2.7.1.1) ; fms-Like Tyrosine Kinase 3 (EC 2.7.10.1) ; TOR Serine-Threonine Kinases (EC 2.7.11.1)
Language	English
Publishing date	2022-01-01
Publishing country	Italy
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2020.257964
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Article ; Online: What do functional genomics tell us about pathogenesis of AML?

Tyner, Jeffrey W / Bottomly, Daniel / Wilmot, Beth / McWeeney, Shannon

Best practice & research. Clinical haematology

2019 Volume 32, Issue 4, Page(s) 101101

Abstract: While molecular genetic abnormalities can tell us much about the pathogenesis of acute myeloid leukemia (AML), these molecular genetics do not always explain drug resistance or sensitivity, leaving room for other mechanisms of tumor pathogenesis outside ... ...

Abstract	While molecular genetic abnormalities can tell us much about the pathogenesis of acute myeloid leukemia (AML), these molecular genetics do not always explain drug resistance or sensitivity, leaving room for other mechanisms of tumor pathogenesis outside of genetic events. The Beat AML 1.0 project was a multicenter project to sequence and functionally query AML samples against over 120 drugs. The results have helped form disease models on how mutations affect disease phenotype and drug sensitivity and have assisted in identifying gene signature profiles that may facilitate selecting the most effective treatment options. However, there are factors outside of genetic abnormalities that affect disease pathogenesis. For example, tumor-associated macrophages in the tumor microenvironment play a role in pathogenesis and represent therapeutic targets.
MeSH term(s)	Gene Expression Profiling ; Gene Expression Regulation, Leukemic ; Genomics ; Humans ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/pathology ; Leukemia, Myeloid, Acute/physiopathology ; Mutation
Language	English
Publishing date	2019-10-18
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2048027-1
ISSN	1532-1924 ; 1521-6926
ISSN (online)	1532-1924
ISSN	1521-6926
DOI	10.1016/j.beha.2019.101101
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Article ; Online: Targeting CCL2/CCR2 signaling overcomes MEK inhibitor resistance in Acute Myeloid Leukemia.

Clinical cancer research : an official journal of the American Association for Cancer Research

2024

Abstract: Purpose: Emerging evidence underscores the critical role of extrinsic factors within the microenvironment in protecting leukemia cells from therapeutic interventions, driving disease progression, and promoting drug resistance in acute myeloid leukemia ( ... ...

Abstract	Purpose: Emerging evidence underscores the critical role of extrinsic factors within the microenvironment in protecting leukemia cells from therapeutic interventions, driving disease progression, and promoting drug resistance in acute myeloid leukemia (AML). This emphasizes the need for the identification of targeted therapies that inhibit intrinsic and extrinsic signaling to overcome drug resistance in AML. Experimental design: We performed a comprehensive analysis utilizing a cohort of ~300 AML patient samples. This analysis encompassed the evaluation of secreted cytokines/growth factors, gene expression, and ex vivo drug sensitivity to small molecules. Our investigation pinpointed a notable association between elevated levels of CCL2 and diminished sensitivity to the MEK inhibitors. We validated this association through loss-of-function and pharmacological inhibition studies. Further, we deployed global phosphoproteomics and CRISPR/Cas9 screening to identify the mechanism of CCR2-mediated MEKi resistance in AML. Results: Our multifaceted analysis unveiled that CCL2 activates multiple pro-survival pathways, including MAPK and cell cycle regulation in MEKi-resistant cells. Employing combination strategies to simultaneously target these pathways heightened growth inhibition in AML cells. Both genetic and pharmacological inhibition of CCR2 sensitized AML cells to trametinib, suppressing proliferation while enhancing apoptosis. These findings underscore a new role for CCL2 in MEKi resistance, offering combination therapies as an avenue to circumvent this resistance. Conclusions: Our study demonstrates a compelling rationale for translating CCL2/CCR2 axis inhibitors in combination with MEK pathway-targeting therapies, as a potent strategy for combating drug resistance in AML. This approach has the potential to enhance the efficacy of treatments to improve AML patient outcomes.
Language	English
Publishing date	2024-03-07
Publishing country	United States
Document type	Journal Article
ZDB-ID	1225457-5
ISSN	1557-3265 ; 1078-0432
ISSN (online)	1557-3265
ISSN	1078-0432
DOI	10.1158/1078-0432.CCR-23-2654
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Article ; Online: Disruption of the MYC Superenhancer Complex by Dual Targeting of FLT3 and LSD1 in Acute Myeloid Leukemia.

Yashar, William M / Curtiss, Brittany M / Coleman, Daniel J / VanCampen, Jake / Kong, Garth / Macaraeg, Jommel / Estabrook, Joseph / Demir, Emek / Long, Nicola / Bottomly, Daniel / McWeeney, Shannon K / Tyner, Jeffrey W / Druker, Brian J / Maxson, Julia E / Braun, Theodore P

Molecular cancer research : MCR

2023 Volume 21, Issue 7, Page(s) 631–647

Abstract: Mutations in Fms-like tyrosine kinase 3 (FLT3) are common drivers in acute myeloid leukemia (AML) yet FLT3 inhibitors only provide modest clinical benefit. Prior work has shown that inhibitors of lysine-specific demethylase 1 (LSD1) enhance kinase ... ...

Abstract	Mutations in Fms-like tyrosine kinase 3 (FLT3) are common drivers in acute myeloid leukemia (AML) yet FLT3 inhibitors only provide modest clinical benefit. Prior work has shown that inhibitors of lysine-specific demethylase 1 (LSD1) enhance kinase inhibitor activity in AML. Here we show that combined LSD1 and FLT3 inhibition induces synergistic cell death in FLT3-mutant AML. Multi-omic profiling revealed that the drug combination disrupts STAT5, LSD1, and GFI1 binding at the MYC blood superenhancer, suppressing superenhancer accessibility as well as MYC expression and activity. The drug combination simultaneously results in the accumulation of repressive H3K9me1 methylation, an LSD1 substrate, at MYC target genes. We validated these findings in 72 primary AML samples with the nearly every sample demonstrating synergistic responses to the drug combination. Collectively, these studies reveal how epigenetic therapies augment the activity of kinase inhibitors in FLT3-ITD (internal tandem duplication) AML. Implications: This work establishes the synergistic efficacy of combined FLT3 and LSD1 inhibition in FLT3-ITD AML by disrupting STAT5 and GFI1 binding at the MYC blood-specific superenhancer complex.
MeSH term(s)	Humans ; Apoptosis ; fms-Like Tyrosine Kinase 3/genetics ; fms-Like Tyrosine Kinase 3/metabolism ; Histone Demethylases/genetics ; Histone Demethylases/metabolism ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/metabolism ; Mutation ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; STAT5 Transcription Factor/metabolism
Chemical Substances	FLT3 protein, human (EC 2.7.10.1) ; fms-Like Tyrosine Kinase 3 (EC 2.7.10.1) ; Histone Demethylases (EC 1.14.11.-) ; Protein Kinase Inhibitors ; STAT5 Transcription Factor
Language	English
Publishing date	2023-03-29
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2098788-2
ISSN	1557-3125 ; 1541-7786
ISSN (online)	1557-3125
ISSN	1541-7786
DOI	10.1158/1541-7786.MCR-22-0745
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Article ; Online: Associating drug sensitivity with differentiation status identifies effective combinations for acute myeloid leukemia.

Kurtz, Stephen E / Eide, Christopher A / Kaempf, Andy / Long, Nicola / Bottomly, Daniel / Nikolova, Olga / Druker, Brian J / McWeeney, Shannon K / Chang, Bill H / Tyner, Jeffrey W / Agarwal, Anupriya

Blood advances

2022 Volume 6, Issue 10, Page(s) 3062–3067

Abstract: Using ex vivo drug screening of primary patient specimens, we identified the combination of the p38 MAPK inhibitor doramapimod (DORA) with the BCL2 inhibitor venetoclax (VEN) as demonstrating broad, enhanced efficacy compared with each single agent ... ...

Abstract	Using ex vivo drug screening of primary patient specimens, we identified the combination of the p38 MAPK inhibitor doramapimod (DORA) with the BCL2 inhibitor venetoclax (VEN) as demonstrating broad, enhanced efficacy compared with each single agent across 335 acute myeloid leukemia (AML) patient samples while sparing primary stromal cells. Single-agent DORA and VEN sensitivity was associated with distinct, nonoverlapping tumor cell differentiation states. In particular, increased monocytes, M4/M5 French-American-British classification, and CD14+ immunophenotype tracked with sensitivity to DORA and resistance to VEN but were mitigated with the combination. Increased expression of MAPK14 and BCL2, the respective primary targets of DORA and VEN, were observed in monocytic and undifferentiated leukemias, respectively. Enrichment for DORA and VEN sensitivities was observed in AML with monocyte-like and progenitor-like transcriptomic signatures, respectively, and these associations diminished with the combination. The mechanism underlying the combination's enhanced efficacy may result from inhibition of p38 MAPK-mediated phosphorylation of BCL2, which in turn enhances sensitivity to VEN. These findings suggest exploiting complementary drug sensitivity profiles with respect to leukemic differentiation state, such as dual targeting of p38 MAPK and BCL2, offers opportunity for broad, enhanced efficacy across the clinically challenging heterogeneous landscape of AML.
MeSH term(s)	Cell Differentiation ; Humans ; Immunophenotyping ; Leukemia, Myeloid, Acute/genetics ; Proto-Oncogene Proteins c-bcl-2/metabolism ; p38 Mitogen-Activated Protein Kinases
Chemical Substances	Proto-Oncogene Proteins c-bcl-2 ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24)
Language	English
Publishing date	2022-01-25
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2915908-8
ISSN	2473-9537 ; 2473-9529
ISSN (online)	2473-9537
ISSN	2473-9529
DOI	10.1182/bloodadvances.2021006307
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Article ; Online: Luxeptinib (CG-806) Targets FLT3 and Clusters of Kinases Operative in Acute Myeloid Leukemia.

Rice, William G / Howell, Stephen B / Zhang, Hongying / Rastgoo, Nasrin / Local, Andrea / Kurtz, Stephen E / Lo, Pierrette / Bottomly, Daniel / Wilmot, Beth / McWeeney, Shannon K / Druker, Brian J / Tyner, Jeffrey W

Molecular cancer therapeutics

2022 Volume 21, Issue 7, Page(s) 1125–1135

Abstract: Luxeptinib (CG-806) simultaneously targets FLT3 and select other kinase pathways operative in myeloid malignancies. We investigated the range of kinases it inhibits, its cytotoxicity landscape ex vivo with acute myeloid leukemia (AML) patient samples, ... ...

Abstract	Luxeptinib (CG-806) simultaneously targets FLT3 and select other kinase pathways operative in myeloid malignancies. We investigated the range of kinases it inhibits, its cytotoxicity landscape ex vivo with acute myeloid leukemia (AML) patient samples, and its efficacy in xenograft models. Luxeptinib inhibits wild-type (WT) and many of the clinically relevant mutant forms of FLT3 at low nanomolar concentrations. It is a more potent inhibitor of the activity of FLT3-internal tandem duplication, FLT3 kinase domain and gatekeeper mutants than against WT FLT3. Broad kinase screens disclosed that it also inhibits other kinases that can drive oncogenic signaling and rescue pathways, but spares kinases known to be associated with clinical toxicity. In vitro profiling of luxeptinib against 186 AML fresh patient samples demonstrated greater potency relative to other FLT3 inhibitors, including cases with mutations in FLT3, isocitrate dehydrogenase-1/2, ASXL1, NPM1, SRSF2, TP53, or RAS, and activity was documented in a xenograft AML model. Luxeptinib administered continuously orally every 12 hours at a dose that yielded a mean Cmin plasma concentration of 1.0 ± 0.3 μmol/L (SEM) demonstrated strong antitumor activity but no myelosuppression or evidence of tissue damage in mice or dogs in acute toxicology studies. On the basis of these studies, luxeptinib was advanced into a phase I trial for patients with AML and myelodysplastic/myeloproliferative neoplasms.
MeSH term(s)	Animals ; Dogs ; Humans ; Leukemia, Myeloid, Acute/drug therapy ; Leukemia, Myeloid, Acute/genetics ; Leukemia, Myeloid, Acute/metabolism ; Mice ; Mutation ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use ; Signal Transduction ; fms-Like Tyrosine Kinase 3/genetics ; fms-Like Tyrosine Kinase 3/metabolism
Chemical Substances	Protein Kinase Inhibitors ; FLT3 protein, human (EC 2.7.10.1) ; fms-Like Tyrosine Kinase 3 (EC 2.7.10.1)
Language	English
Publishing date	2022-04-30
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2063563-1
ISSN	1538-8514 ; 1535-7163
ISSN (online)	1538-8514
ISSN	1535-7163
DOI	10.1158/1535-7163.MCT-21-0832
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Zs.A 5750: Show issues

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Article ; Online: Dual BTK/SYK inhibition with CG-806 (luxeptinib) disrupts B-cell receptor and Bcl-2 signaling networks in mantle cell lymphoma.

Thieme, Elana / Liu, Tingting / Bruss, Nur / Roleder, Carly / Lam, Vi / Wang, Xiaoguang / Nechiporuk, Tamilla / Shouse, Geoffrey / Danilova, Olga V / Bottomly, Daniel / McWeeney, Shannon K / Tyner, Jeffrey W / Kurtz, Stephen E / Danilov, Alexey V

Cell death & disease

2022 Volume 13, Issue 3, Page(s) 246

Abstract: Aberrant B-cell receptor (BCR) signaling is a key driver in lymphoid malignancies. Bruton tyrosine kinase (BTK) inhibitors that disrupt BCR signaling have received regulatory approvals in therapy of mantle cell lymphoma (MCL). However, responses are ... ...

Abstract	Aberrant B-cell receptor (BCR) signaling is a key driver in lymphoid malignancies. Bruton tyrosine kinase (BTK) inhibitors that disrupt BCR signaling have received regulatory approvals in therapy of mantle cell lymphoma (MCL). However, responses are incomplete and patients who experience BTK inhibitor therapy failure have dire outcomes. CG-806 (luxeptinib) is a dual BTK/SYK inhibitor in clinical development in hematologic malignancies. Here we investigated the pre-clinical activity of CG-806 in MCL. In vitro treatment with CG-806 thwarted survival of MCL cell lines and patient-derived MCL cells in a dose-dependent manner. CG-806 blocked BTK and SYK activation and abrogated BCR signaling. Contrary to ibrutinib, CG-806 downmodulated the anti-apoptotic proteins Mcl-1 and Bcl-xL, abrogated survival of ibrutinib-resistant MCL cell lines, and partially reversed the pro-survival effects of stromal microenvironment-mimicking conditions in primary MCL cells. Dual BTK/SYK inhibition led to mitochondrial membrane depolarization accompanied by mitophagy and metabolic reprogramming toward glycolysis. In vivo studies of CG-806 demonstrated improved survival in one of the two tested aggressive MCL PDX models. While suppression of the anti-apoptotic Bcl-2 family proteins and NFκB signaling correlated with in vivo drug sensitivity, OxPhos and MYC transcriptional programs were upregulated in the resistant model following treatment with CG-806. BAX and NFKBIA were implicated in susceptibility to CG-806 in a whole-genome CRISPR-Cas9 library screen (in a diffuse large B-cell lymphoma cell line). A high-throughput in vitro functional drug screen demonstrated synergy between CG-806 and Bcl-2 inhibitors. In sum, dual BTK/SYK inhibitor CG-806 disrupts BCR signaling and induces metabolic reprogramming and apoptosis in MCL. The Bcl-2 network is a key mediator of sensitivity to CG-806 and combined targeting of Bcl-2 demonstrates synergy with CG-806 warranting continued exploration in lymphoid malignancies.
MeSH term(s)	Adult ; Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors ; Cell Line, Tumor ; Humans ; Lymphoma, Mantle-Cell/drug therapy ; Lymphoma, Mantle-Cell/genetics ; Lymphoma, Mantle-Cell/metabolism ; Protein Kinase Inhibitors/pharmacology ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Pyrazoles/pharmacology ; Pyrimidines/pharmacology ; Pyrimidines/therapeutic use ; Receptors, Antigen, B-Cell/metabolism ; Syk Kinase ; Tumor Microenvironment
Chemical Substances	BCL2 protein, human ; Protein Kinase Inhibitors ; Proto-Oncogene Proteins c-bcl-2 ; Pyrazoles ; Pyrimidines ; Receptors, Antigen, B-Cell ; Agammaglobulinaemia Tyrosine Kinase (EC 2.7.10.2) ; BTK protein, human (EC 2.7.10.2) ; SYK protein, human (EC 2.7.10.2) ; Syk Kinase (EC 2.7.10.2)
Language	English
Publishing date	2022-03-16
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2541626-1
ISSN	2041-4889 ; 2041-4889
ISSN (online)	2041-4889
ISSN	2041-4889
DOI	10.1038/s41419-022-04684-1
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Article ; Online: Monocytic differentiation and AHR signaling as Primary Nodes of BET Inhibitor Response in Acute Myeloid Leukemia.

Romine, Kyle A / Nechiporuk, Tamilla / Bottomly, Daniel / Jeng, Sophia / McWeeney, Shannon K / Kaempf, Andy / Corces, M Ryan / Majeti, Ravindra / Tyner, Jeffrey W

Blood cancer discovery

2021 Volume 2, Issue 5, Page(s) 518–531

Abstract: To understand mechanisms of response to BET inhibitors (BETi), we mined the Beat AML functional genomic dataset and performed genome-wide CRISPR screens on BETi- sensitive and BETi- resistant AML cells. Both strategies revealed regulators of monocytic ... ...

Abstract	To understand mechanisms of response to BET inhibitors (BETi), we mined the Beat AML functional genomic dataset and performed genome-wide CRISPR screens on BETi- sensitive and BETi- resistant AML cells. Both strategies revealed regulators of monocytic differentiation, SPI1, JUNB, FOS, and aryl-hydrocarbon receptor signaling (AHR/ARNT), as determinants of BETi response. AHR activation synergized with BETi while inhibition antagonized BETi-mediated cytotoxicity. Consistent with BETi sensitivity dependence on monocytic differentiation,
MeSH term(s)	Antineoplastic Agents/pharmacology ; Cell Line, Tumor ; HL-60 Cells ; Humans ; Leukemia, Myeloid, Acute/drug therapy ; Signal Transduction
Chemical Substances	Antineoplastic Agents
Language	English
Publishing date	2021-07-01
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3028898-8
ISSN	2643-3249 ; 2643-3230
ISSN (online)	2643-3249
ISSN	2643-3230
DOI	10.1158/2643-3230.BCD-21-0012
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Article ; Online: Monocytic differentiation and AHR signaling as Primary Nodes of BET Inhibitor Response in Acute Myeloid Leukemia.

Romine, Kyle A / Nechiporuk, Tamilla / Bottomly, Daniel / Jeng, Sophia / McWeeney, Shannon K / Kaempf, Andy / Corces, M Ryan / Majeti, Ravindra / Tyner, Jeffrey W

Cancer discovery

2021

Abstract	To understand mechanisms of response to BET inhibitors (BETi), we mined the Beat AML functional genomic dataset and performed genome-wide CRISPR screens on BETi- sensitive and BETi- resistant AML cells. Both strategies revealed regulators of monocytic differentiation, SPI1, JUNB, FOS, and aryl-hydrocarbon receptor signaling (AHR/ARNT), as determinants of BETi response. AHR activation synergized with BETi while inhibition antagonized BETi-mediated cytotoxicity. Consistent with BETi sensitivity dependence on monocytic differentiation, ex vivo sensitivity to BETi in primary AML patient samples correlated with higher expression of monocytic markers CSF1R, LILRs, and VCAN. In addition, HL-60 cell line differentiation enhanced its sensitivity to BETi. Further, screens to rescue BETi sensitivity identified BCL2 and CDK6 as druggable vulnerabilities. Finally, monocytic AML patient samples refractory to venetoclax ex vivo were significantly more sensitive to combined BETi + venetoclax. Together, our work highlights mechanisms that could predict BETi response and identifies combination strategies to overcome resistance.
Language	English
Publishing date	2021-07-01
Publishing country	United States
Document type	Journal Article
ZDB-ID	2625242-9
ISSN	2159-8290 ; 2159-8274
ISSN (online)	2159-8290
ISSN	2159-8274
DOI	10.1158/2643-3230.BCD-21-0012
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