Aberrant signaling triggered by oncogenic or hyperactive
RAS proteins contributes to the malignant phenotypes in a significant percentage of myeloid
malignancies. Of these,
juvenile myelomonocytic leukemia (JMML), an aggressive childhood
cancer, is largely driven by mutations in RAS genes and those that encode regulators of these
proteins. The Mx1-cre kras+/G12D mouse model mirrors several key features of this disease and has been used extensively to determine the utility and mechanism of small molecule
therapeutics in the context of RAS-driven
myeloproliferative disorders. Treatment of disease-bearing KRASG12D mice with
rigosertib (RGS), a small molecule RAS mimetic that is in phase II and III clinical trials for MDS and AML, decreased the severity of
leukocytosis and
splenomegaly and extended their survival. RGS also increased the frequency of HSCs and rebalanced the ratios of myeloid progenitors. Further analysis of KRASG12D HSPCs in vitro revealed that RGS suppressed hyperproliferation in response to
GM-CSF and inhibited the phosphorylation of key RAS effectors. Together, these data suggest that RGS might be of clinical benefit in RAS-driven myeloid disorders.