title: Enhanced MAPK signaling is essential for CSF3R-induced leukemia.
abstract: Both membrane-proximal and truncation mutations in CSF3R have recently been reported to drive the onset of chronic neutrophilic leukemia (CNL). Here we show that although truncation mutation alone cannot induce leukemia, both proximal and compound mutations (proximal and truncation mutations on same allele) are leukemogenic with a disease latency of 90 and 23 days, respectively. Comparative whole-genome expression profiling and biochemical experiments revealed that induced expression of Mapk adaptor protein Ksr1 and enhanced Mapk signaling are crucial to leukemogenesis by CSF3R proximal and compound mutants. Moreover, inhibition of Mek1/2 by trametinib alone is sufficient to suppress leukemia induced by both CSF3R proximal and ruxolitinib-resistant compound mutations. Together, these findings elucidate a Mapk-dependent mechanism of CSF3R-induced pathogenesis, and they establish the rationale for clinical evaluation of MEK1/2 inhibition in CNL.
authors.affiliation: Division of Experimental Hematology and Cancer Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: S
authors.initials: S
authors.lastname: Rohrabaugh
authors.affiliation: Division of Experimental Hematology and Cancer Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: M
authors.initials: M
authors.lastname: Kesarwani
authors.affiliation: Division of Experimental Hematology and Cancer Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Kincaid
authors.affiliation: Division of Experimental Hematology and Cancer Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: E
authors.initials: E
authors.lastname: Huber
authors.affiliation: Division of Experimental Hematology and Cancer Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: J
authors.initials: J
authors.lastname: Leddonne
authors.affiliation: Division of Experimental Hematology and Cancer Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Siddiqui
authors.affiliation: Division of Experimental Hematology and Cancer Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Khalifa
authors.affiliation: Division of Experimental Hematology and Cancer Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: K
authors.initials: K
authors.lastname: Komurov
authors.affiliation: Division of Experimental Hematology and Cancer Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.|Division of Immunobiology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: H L
authors.initials: HL
authors.lastname: Grimes
authors.affiliation: Division of Experimental Hematology and Cancer Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.|Division of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.|College of Medicine, Department of Pathology, University of Cincinnati, Cincinnati, OH, USA.
authors.forename: M
authors.initials: M
authors.lastname: Azam
mesh_terms: D000818:Animals; D006801:Humans; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors; D007938:Leukemia / Q000209:etiology*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D011728:Pyridones / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D016184:Receptors, Colony-Stimulating Factor / Q000235:genetics / Q000502:physiology*
chemical_list: C517047:CSF3R protein, human; D011728:Pyridones; D011744:Pyrimidinones; D016184:Receptors, Colony-Stimulating Factor; C560077:trametinib; D053614:Janus Kinase 2; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2