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 and Kapil N Bhalla

Key Points

  • Depleting RUNX1 or editing-out RUNX1 eR1, or treatment with BET protein antagonist induces lethality in AML expressing mtRUNX1.

  • Expression-mimickers of RUNX1-depletion induce more lethality in HPCs expressing germline mtRUNX1 from FPD-AML than HPCs from FPD.


RUNX1 transcription factor regulates normal and malignant hematopoiesis. Somatic or germline mutant (mt) RUNX1 is associated with poorer outcome in AML. Knockdown or inhibition of RUNX1 induced more apoptosis of AML expressing mutant versus wild-type (wt) 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 shRNA, repressed RUNX1, inhibited cell growth and induced cell lethality in AML cells expressing mtRUNX1. Moreover, treatment with BET protein inhibitor (BETi) or degrader (BET-PROTAC) repressed RUNX1 and its targets, inducing apoptosis, and improving survival of mice engrafted with AML expressing mtRUNX1. LINCS1000-CMap datasets queried with mRNA signature of RUNX1 knockdown identified novel expression-mimickers (EMs), which repressed RUNX1 and exerted in vitro and in vivo efficacy against AML cells expressing mtRUNX1. Additionally, the EMs cinobufagin, anisomycin and narciclasine induced more lethality in hematopoietic progenitor cells (HPCs) expressing germ-line mtRUNX1 from patients with AML as compared to HPCs from patients with Familial Platelet Disorder (FPD), or normal untransformed HPCs. These findings highlight novel therapeutic agents for AML expressing somatic or germline mtRUNX1.

  • Submitted December 25, 2018.
  • Revision received April 16, 2019.
  • Accepted April 16, 2019.