RUNX1|General AML

AACR 2017: Poster LB-081/6 – RUNX1- targeted therapy for AML with RUNX1 mutation

A late breaking research poster session titled “Molecular and Cellular Biology 2” took place at the 107th American Association for Cancer Research (AACR) annual meeting in Washington, DC, USA, on Monday 3rd April. During this session, Mill et al. from the MD Anderson Cancer Center displayed their poster (LB-081/6) titled “Novel and effective RUNX1-targeted therapy for AML expressing RUNX1 mutation”.

Somatic mutations in RUNX1 (mtRUNX1) are associated with resistance to standard chemotherapy and poor prognosis in Acute Myeloid Leukemia (AML) patients. Mill et al. aimed to develop a novel targeted therapy for AML expressing mtRUNX1.

The key results were:
  • In OCI-AML5 cells (mutant RUNX1 AML cell line), shRNA depletion of RUNX1 led to an attenuation of RUNX1 target gene expression, inhibition of cell proliferation, and an increase in apoptosis  
  • Depletion of Bromodomain-Containing Protein 4 (BRD4) in OCI-AML5 cells led to a decrease in RUNX1 expression, inhibition of cell proliferation, and an increase in apoptosis
  • OTX015 (Bromodomain and Extra-Terminal [BET] Protein [BETP] inhibitor) reduced BRD4 occupancy at the enhancer and promoter of RUNX1 in OCI-AML5 cells
  • Treatment of NSG mice engrafted with luciferase-transduced OCI-AML5 cells with OTX015 reduced the AML burden and significantly improved their survival (P < 0.01)
  • Co-treatment with the OTX015 and ABT-199 (BCL2 inhibitor) or palbociclib (CDK4/6 inhibitor) or decitabine synergistically induced apoptosis of OCI-AML5 and PD AML BPCs

In summation, BETP antagonist-based therapy for AML expressing mtRUNX1 was effective either alone or in combination therapy.

References
  1. Mill C.P. et al. Novel and effective RUNX1-targeted therapy for AML expressing RUNX1 mutation [Poster]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2017 Apr 1–5; Washington, DC. Philadelphia (PA): AACR; 2017. Poster nr [LB-081/6].