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- Title
Combined MEK and JAK inhibition abrogates murine myeloproliferative neoplasm.
- Authors
Guangyao Kong; Wunderlich, Mark; Yang, David; Ranheim, Erik A.; Young, Ken H.; Jinyong Wang; Yuan-I Chang; Juan Du; Yangang Liu; Sin Ruow Tey; Xinmin Zhang; Juckett, Mark; Mattison, Ryan; Damnernsawad, Alisa; Jingfang Zhang; Mulloy, James C.; Jing Zhang
- Abstract
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.
- Subjects
LEUKEMIA; CANCER chemotherapy; CELLS; LABORATORY mice; GROWTH factors
- Publication
Journal of Clinical Investigation, 2014, Vol 124, Issue 6, p2762
- ISSN
0021-9738
- Publication type
Article
- DOI
10.1172/JCI74182