MedicalResearch.com Interview with: Eirini Papapetrou, MD, PhD Professor of Oncological Sciences Professor of Medicine, Hematology and Medical Oncology Director, Center for Advancement of Blood Cancer Therapies Co-Director, Stem Cell Engineering Core Icahn School of Medicine at Mount Sinai New York, NY 10029   MedicalResearch.com: What is the background for this study? What are the main findings? Response: RAS in the most commonly mutated oncogene in human cancers. Particularly in acute myeloid leukemia, about one third of cases have RAS mutations. We set out to understand the role of these mutations in the development of leukemia and in response to treatment. We found that RAS mutations happen late in the course of the disease as progression mutations because they are acquired by more mature leukemic cells coming from preexisting leukemia stem cells (LSCs). Importantly, these more mature cells, upon acquisition of RAS mutations, become leukemia stem cells (LSCs) with different properties than the previous LSCs. Most critically, they develop resistance to a recently FDA-approved drug for the treatment of leukemia, venetoclax (VEN). In addition, these RAS-mutated LSCs give rise to leukemia cells with monocytic differentiation. Both RAS mutations and monocytic differentiation of AML have previously been associated with VEN resistance in clinical studies. We show that it is the RAS mutations that cause both the monocytic differentiation and the VEN resistance. Thus, poor patient outcomes after VEN therapy are driven by RAS mutations and not by monocytic disease.  (more…)