title: Combined MEK and JAK inhibition abrogates murine myeloproliferative neoplasm.
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.
authors.forename: Guangyao
authors.initials: G
authors.lastname: Kong
authors.forename: Mark
authors.initials: M
authors.lastname: Wunderlich
authors.forename: David
authors.initials: D
authors.lastname: Yang
authors.forename: Erik A
authors.initials: EA
authors.lastname: Ranheim
authors.forename: Ken H
authors.initials: KH
authors.lastname: Young
authors.forename: Jinyong
authors.initials: J
authors.lastname: Wang
authors.forename: Yuan-I
authors.initials: YI
authors.lastname: Chang
authors.forename: Juan
authors.initials: J
authors.lastname: Du
authors.forename: Yangang
authors.initials: Y
authors.lastname: Liu
authors.forename: Sin Ruow
authors.initials: SR
authors.lastname: Tey
authors.forename: Xinmin
authors.initials: X
authors.lastname: Zhang
authors.forename: Mark
authors.initials: M
authors.lastname: Juckett
authors.forename: Ryan
authors.initials: R
authors.lastname: Mattison
authors.forename: Alisa
authors.initials: A
authors.lastname: Damnernsawad
authors.forename: Jingfang
authors.initials: J
authors.lastname: Zhang
authors.forename: James C
authors.initials: JC
authors.lastname: Mulloy
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D011905:Genes, ras; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors*; D015477:Leukemia, Myelomonocytic, Chronic / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D054429:Leukemia, Myelomonocytic, Juvenile / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008817:Mice, Mutant Strains; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D009196:Myeloproliferative Disorders / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D047428:Protein Kinase Inhibitors; D053612:Janus Kinases; D020929:Mitogen-Activated Protein Kinase Kinases