RUNX1-targeted therapy for AML expressing somatic or germline mutation in RUNX1

Christopher P. Mill; Warren Fiskus; Courtney D. DiNardo; Yimin Qian; Kanak Raina; Kimal Rajapakshe; Dimuthu Perera; Cristian Coarfa; Tapan M. Kadia; Joseph D. Khoury; Dyana T. Saenz; David N. Saenz; Anuradha Illendula; Koichi Takahashi; Steven M. Kornblau; Michael R. Green; Andrew P. Futreal; John H. Bushweller; Craig M. Crews; Kapil N. Bhalla

doi:10.1182/blood.2018893982

RUNX1-targeted therapy for AML expressing somatic or germline mutation in RUNX1

Christopher P. Mill, Warren Fiskus, Courtney D. DiNardo, Yimin Qian, Kanak Raina, Kimal Rajapakshe, Dimuthu Perera, Cristian Coarfa, Tapan M. Kadia, Joseph D. Khoury, Dyana T. Saenz, David N. Saenz, Anuradha Illendula, Koichi Takahashi, Steven M. Kornblau, Michael R. Green, Andrew P. Futreal, John H. Bushweller, Craig M. Crews, Kapil N. Bhalla

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71 Scopus citations

Abstract

RUNX1 transcription factor regulates normal and malignant hematopoiesis. Somatic or germline mutant RUNX1 (mtRUNX1) is associated with poorer outcome in acute myeloid leukemia (AML). Knockdown or inhibition of RUNX1 induced more apoptosis of AML expressing mtRUNX1 versus wild-type RUNX1 and improved survival of mice engrafted with mtRUNX1-expressing AML. CRISPR/Cas9-mediated editing-out of RUNX1 enhancer (eR1) within its intragenic super-enhancer, or BET protein BRD4 depletion by short hairpin RNA, repressed RUNX1, inhibited cell growth, and induced cell lethality in AML cells expressing mtRUNX1. Moreover, treatment with BET protein inhibitor or degrader (BET-proteolysis targeting chimera) repressed RUNX1 and its targets, inducing apoptosis and improving survival of mice engrafted with AML expressing mtRUNX1. Library of Integrated Network-based Cellular Signatures 1000-connectivity mapping data sets queried with messenger RNA signature of RUNX1 knockdown identified novel expressionmimickers (EMs), which repressed RUNX1 and exerted in vitro and in vivo efficacy against AML cells expressing mtRUNX1. In addition, the EMs cinobufagin, anisomycin, and narciclasine induced more lethality in hematopoietic progenitor cells (HPCs) expressing germline mtRUNX1 from patients with AML compared with HPCs from patients with familial platelet disorder (FPD), or normal untransformed HPCs. These findings highlight novel therapeutic agents forAML expressing somatic or germline mtRUNX1.

Original language	English (US)
Pages (from-to)	59-73
Number of pages	15
Journal	Blood
Volume	134
Issue number	1
DOIs	https://doi.org/10.1182/blood.2018893982
State	Published - Jul 4 2019

ASJC Scopus subject areas

Biochemistry
Immunology
Hematology
Cell Biology

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10.1182/blood.2018893982

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Mill, C. P., Fiskus, W., DiNardo, C. D., Qian, Y., Raina, K., Rajapakshe, K., Perera, D., Coarfa, C., Kadia, T. M., Khoury, J. D., Saenz, D. T., Saenz, D. N., Illendula, A., Takahashi, K., Kornblau, S. M., Green, M. R., Futreal, A. P., Bushweller, J. H., Crews, C. M., & Bhalla, K. N. (2019). RUNX1-targeted therapy for AML expressing somatic or germline mutation in RUNX1. Blood, 134(1), 59-73. https://doi.org/10.1182/blood.2018893982

Mill, CP , Fiskus, W , DiNardo, CD, Qian, Y, Raina, K, Rajapakshe, K, Perera, D, Coarfa, C, Kadia, TM, Khoury, JD, Saenz, DT, Saenz, DN, Illendula, A, Takahashi, K , Kornblau, SM , Green, MR , Futreal, AP, Bushweller, JH, Crews, CM & Bhalla, KN 2019, 'RUNX1-targeted therapy for AML expressing somatic or germline mutation in RUNX1', Blood, vol. 134, no. 1, pp. 59-73. https://doi.org/10.1182/blood.2018893982

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title = "RUNX1-targeted therapy for AML expressing somatic or germline mutation in RUNX1",

abstract = "RUNX1 transcription factor regulates normal and malignant hematopoiesis. Somatic or germline mutant RUNX1 (mtRUNX1) is associated with poorer outcome in acute myeloid leukemia (AML). Knockdown or inhibition of RUNX1 induced more apoptosis of AML expressing mtRUNX1 versus wild-type RUNX1 and improved survival of mice engrafted with mtRUNX1-expressing AML. CRISPR/Cas9-mediated editing-out of RUNX1 enhancer (eR1) within its intragenic super-enhancer, or BET protein BRD4 depletion by short hairpin RNA, repressed RUNX1, inhibited cell growth, and induced cell lethality in AML cells expressing mtRUNX1. Moreover, treatment with BET protein inhibitor or degrader (BET-proteolysis targeting chimera) repressed RUNX1 and its targets, inducing apoptosis and improving survival of mice engrafted with AML expressing mtRUNX1. Library of Integrated Network-based Cellular Signatures 1000-connectivity mapping data sets queried with messenger RNA signature of RUNX1 knockdown identified novel expressionmimickers (EMs), which repressed RUNX1 and exerted in vitro and in vivo efficacy against AML cells expressing mtRUNX1. In addition, the EMs cinobufagin, anisomycin, and narciclasine induced more lethality in hematopoietic progenitor cells (HPCs) expressing germline mtRUNX1 from patients with AML compared with HPCs from patients with familial platelet disorder (FPD), or normal untransformed HPCs. These findings highlight novel therapeutic agents forAML expressing somatic or germline mtRUNX1.",

author = "Mill, {Christopher P.} and Warren Fiskus and DiNardo, {Courtney D.} and Yimin Qian and Kanak Raina and Kimal Rajapakshe and Dimuthu Perera and Cristian Coarfa and Kadia, {Tapan M.} and Khoury, {Joseph D.} and Saenz, {Dyana T.} and Saenz, {David N.} and Anuradha Illendula and Koichi Takahashi and Kornblau, {Steven M.} and Green, {Michael R.} and Futreal, {Andrew P.} and Bushweller, {John H.} and Crews, {Craig M.} and Bhalla, {Kapil N.}",

note = "Publisher Copyright: {\textcopyright} 2019 by The American Society of Hematology.",

year = "2019",

month = jul,

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doi = "10.1182/blood.2018893982",

language = "English (US)",

volume = "134",

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T1 - RUNX1-targeted therapy for AML expressing somatic or germline mutation in RUNX1

AU - Mill, Christopher P.

AU - Fiskus, Warren

AU - DiNardo, Courtney D.

AU - Qian, Yimin

AU - Raina, Kanak

AU - Rajapakshe, Kimal

AU - Perera, Dimuthu

AU - Coarfa, Cristian

AU - Kadia, Tapan M.

AU - Khoury, Joseph D.

AU - Saenz, Dyana T.

AU - Saenz, David N.

AU - Illendula, Anuradha

AU - Takahashi, Koichi

AU - Kornblau, Steven M.

AU - Green, Michael R.

AU - Futreal, Andrew P.

AU - Bushweller, John H.

AU - Crews, Craig M.

AU - Bhalla, Kapil N.

PY - 2019/7/4

Y1 - 2019/7/4

N2 - RUNX1 transcription factor regulates normal and malignant hematopoiesis. Somatic or germline mutant RUNX1 (mtRUNX1) is associated with poorer outcome in acute myeloid leukemia (AML). Knockdown or inhibition of RUNX1 induced more apoptosis of AML expressing mtRUNX1 versus wild-type RUNX1 and improved survival of mice engrafted with mtRUNX1-expressing AML. CRISPR/Cas9-mediated editing-out of RUNX1 enhancer (eR1) within its intragenic super-enhancer, or BET protein BRD4 depletion by short hairpin RNA, repressed RUNX1, inhibited cell growth, and induced cell lethality in AML cells expressing mtRUNX1. Moreover, treatment with BET protein inhibitor or degrader (BET-proteolysis targeting chimera) repressed RUNX1 and its targets, inducing apoptosis and improving survival of mice engrafted with AML expressing mtRUNX1. Library of Integrated Network-based Cellular Signatures 1000-connectivity mapping data sets queried with messenger RNA signature of RUNX1 knockdown identified novel expressionmimickers (EMs), which repressed RUNX1 and exerted in vitro and in vivo efficacy against AML cells expressing mtRUNX1. In addition, the EMs cinobufagin, anisomycin, and narciclasine induced more lethality in hematopoietic progenitor cells (HPCs) expressing germline mtRUNX1 from patients with AML compared with HPCs from patients with familial platelet disorder (FPD), or normal untransformed HPCs. These findings highlight novel therapeutic agents forAML expressing somatic or germline mtRUNX1.

AB - RUNX1 transcription factor regulates normal and malignant hematopoiesis. Somatic or germline mutant RUNX1 (mtRUNX1) is associated with poorer outcome in acute myeloid leukemia (AML). Knockdown or inhibition of RUNX1 induced more apoptosis of AML expressing mtRUNX1 versus wild-type RUNX1 and improved survival of mice engrafted with mtRUNX1-expressing AML. CRISPR/Cas9-mediated editing-out of RUNX1 enhancer (eR1) within its intragenic super-enhancer, or BET protein BRD4 depletion by short hairpin RNA, repressed RUNX1, inhibited cell growth, and induced cell lethality in AML cells expressing mtRUNX1. Moreover, treatment with BET protein inhibitor or degrader (BET-proteolysis targeting chimera) repressed RUNX1 and its targets, inducing apoptosis and improving survival of mice engrafted with AML expressing mtRUNX1. Library of Integrated Network-based Cellular Signatures 1000-connectivity mapping data sets queried with messenger RNA signature of RUNX1 knockdown identified novel expressionmimickers (EMs), which repressed RUNX1 and exerted in vitro and in vivo efficacy against AML cells expressing mtRUNX1. In addition, the EMs cinobufagin, anisomycin, and narciclasine induced more lethality in hematopoietic progenitor cells (HPCs) expressing germline mtRUNX1 from patients with AML compared with HPCs from patients with familial platelet disorder (FPD), or normal untransformed HPCs. These findings highlight novel therapeutic agents forAML expressing somatic or germline mtRUNX1.

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RUNX1-targeted therapy for AML expressing somatic or germline mutation in RUNX1

Abstract

ASJC Scopus subject areas

MD Anderson CCSG core facilities

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