[HTML][HTML] Combined MEK and JAK inhibition abrogates murine myeloproliferative neoplasm
G Kong, M Wunderlich, D Yang… - The Journal of …, 2014 - Am Soc Clin Investig
The Journal of clinical investigation, 2014•Am Soc Clin Investig
Overactive 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 (NrasG12D/G12D) in murine hematopoietic cells promotes an acute
myeloproliferative neoplasm (MPN) that recapitulates many features of JMML and MP-
CMML. We found that NrasG12D/G12D-expressing HSCs, which serve as JMML/MP-CMML …
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 (NrasG12D/G12D) in murine hematopoietic cells promotes an acute
myeloproliferative neoplasm (MPN) that recapitulates many features of JMML and MP-
CMML. We found that NrasG12D/G12D-expressing HSCs, which serve as JMML/MP-CMML …
Overactive 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 (NrasG12D/G12D) in murine hematopoietic cells promotes an acute myeloproliferative neoplasm (MPN) that recapitulates many features of JMML and MP-CMML. We found that NrasG12D/G12D-expressing HSCs, which serve as JMML/MP-CMML–initiating 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 NrasG12D/G12D-expressing HSCs but failed to restore their proper function. Consequently, approximately 60% of NrasG12D/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 NrasG12D/G12D-expressing HSC function in vivo, and promoted long-term survival without evident disease manifestation in NrasG12D/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.
The Journal of Clinical Investigation