Abstract B22: Combined MEK and JAK inhibition rescues mutant hematopoietic stem cell function and provides long-term survival in NrasG12D/G12D mice

Overactive Ras signaling is prevalent in human juvenile and chronic myelomonocytic leukemias (JMML/CMML) that are refractory to conventional chemotherapy. Conditional activation of endogenous Nras G12D/G12D in hematopoietic cells of mice leads to an acute myeloproliferative disease (MPN) that recapitulates many features of JMML and myeloproliferative variant of CMML. We found that as JMML/CMML initiating cells, Nras G12D/G12D hematopoietic stem cells (HSCs) show strong ERK1/2 hyperactivation, hyperproliferation, and depletion with concomitant expansion of downstream progenitors. MEK pathway inhibition alone prolongs the presence of mutant HSCs, but fails to restore their proper function. Consequently, ∼60% of Nras G12D/G12D mice treated with MEK inhibitor alone died within 20 weeks and the remaining animals also displayed significant JMML/CMML-like phenotypes. In contrast, simultaneous inhibition of JAK/STAT signaling, a commonly hyperactivated pathway in human and mouse CMML, more potently inhibits human and mouse CMML cell growth in vitro, sustainably rescues mutant HSC function in vivo, and promotes long-term survival without evident disease manifestation in Nras G12D/G12D mice. Our results provide a strong rationale for combined targeting of MEK/ERK and JAK/STAT in treating JMML and CMML patients. Citation Format: Guangyao Kong, Wunderlich Mark, David Yang, Erik A. Ranheim, Ken H. Young, Jinyong Wang, Yuan-I Chang, Juan Du, Yangang Liu, Sin Ruow Tey, Xinmin Zhang, Mark Juckett, Ryan Mattison, Alisa Damnernsawad, Jingfang Zhang, James C. Mulloy, Jing Zhang. Combined MEK and JAK inhibition rescues mutant hematopoietic stem cell function and provides long-term survival in NrasG12D/G12D mice. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr B22. doi: 10.1158/1557-3125.RASONC14-B22