Combined MEK and JAK inhibition abrogates murine myeloproliferative neoplasm

RAS signaling is prevalent in juvenile myelomonocytic leukemia (JMML) and the myeloproliferative variant of chronic myelomonocytic leukemia (MP-CMML) in humans, and both are refractory to conventional chemotherapy. Conditional activation of a constitutively active oncogenic Nras (Nras(G12D/G12D)) in murine hematopoietic cells promotes an acute myeloproliferative neoplasm (MPN) that recapitulates many features of JMML and MP-CMML. We found that Nras(Gl2D/G12D)-expressing HSCs, which serve as JMML/MP-CMMLinitiating cells, show strong hyperactivation of ERK1/2, promoting hyperproliferation and depletion of HSCs and expansion of downstream progenitors. Inhibition of the MEK pathway alone prolonged the presence of Nras(G12D/G12D)- expressing HSCs but failed to restore their proper function. Consequently, approximately 60% of Nras(GI2D/G12D) mice treated with MEK inhibitor alone died within 20 weeks, and the remaining animals continued to display JMML/MP-CMML-like phenotypes. In contrast, combined inhibition of MEK and. JAK/ STAT signaling, which is commonly hyperactivated in human and mouse CMML, potently inhibited human and mouse CMML cell growth in vitro, rescued mutant Nras(G12D/G12D)-expressing HSC function in vivo, and promoted long-term survival without evident disease manifestation in Nras(G12D/G12D) animals. These results provide a strong rationale for further exploration of combined targeting of MEK/ERK and. JAK/STAT in treating patients with JMML and MP-CMML.