title: Normal hematopoiesis and neurofibromin-deficient myeloproliferative disease require Erk.
abstract: Neurofibromatosis type 1 (NF1) predisposes individuals to the development of juvenile myelomonocytic leukemia (JMML), a fatal myeloproliferative disease (MPD). In genetically engineered murine models, nullizygosity of Nf1, a tumor suppressor gene that encodes a Ras-GTPase-activating protein, results in hyperactivity of Raf/Mek/Erk in hematopoietic stem and progenitor cells (HSPCs). Activated Erk1/2 phosphorylate kinases and transcription factors with myriad mitogenic roles in diverse cell types. However, genetic studies examining Erk1/2's differential and/or combined control of normal and Nf1-deficient myelopoiesis are lacking. Moreover, prior studies relying on chemical Mek/Erk inhibitors have reached conflicting conclusions in normal and Nf1-deficient mice. Here, we show that while single Erk1 or Erk2 disruption did not grossly compromise myelopoiesis, dual Erk1/2 disruption rapidly ablated granulocyte and monocyte production in vivo, diminished progenitor cell number, and prevented HSPC proliferation in vitro. Genetic disruption of Erk1/2 in the context of Nf1 nullizygosity (Mx1Cre(+)Nf1(flox/flox)Erk1(-/-)Erk2(flox/flox)) fully protects against the development of MPD. Collectively, we identified a fundamental requirement for Erk1/2 signaling in normal and Nf1-deficient hematopoiesis, elucidating a critical hematopoietic function for Erk1/2 while genetically validating highly selective Mek/Erk inhibitors in a leukemia that is otherwise resistant to traditional therapy.
authors.affiliation: Herman Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana, USA.
authors.forename: Karl
authors.initials: K
authors.lastname: Staser
authors.forename: Su-Jung
authors.initials: SJ
authors.lastname: Park
authors.forename: Steven D
authors.initials: SD
authors.lastname: Rhodes
authors.forename: Yi
authors.initials: Y
authors.lastname: Zeng
authors.forename: Yong Zheng
authors.initials: YZ
authors.lastname: He
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Shew
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Gehlhausen
authors.forename: Donna
authors.initials: D
authors.lastname: Cerabona
authors.forename: Keshav
authors.initials: K
authors.lastname: Menon
authors.forename: Shi
authors.initials: S
authors.lastname: Chen
authors.forename: Zejin
authors.initials: Z
authors.lastname: Sun
authors.forename: Jin
authors.initials: J
authors.lastname: Yuan
authors.forename: David A
authors.initials: DA
authors.lastname: Ingram
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Nalepa
authors.forename: Feng-Chun
authors.initials: FC
authors.lastname: Yang
authors.forename: D Wade
authors.initials: DW
authors.lastname: Clapp
mesh_terms: D000818:Animals; D054429:Leukemia, Myelomonocytic, Juvenile / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D048052:Mitogen-Activated Protein Kinase 3 / Q000235:genetics / Q000378:metabolism*; D038042:Myelopoiesis; D009456:Neurofibromatosis 1 / Q000150:complications / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D025542:Neurofibromin 1
chemical_list: D025542:Neurofibromin 1; D048052:Mitogen-Activated Protein Kinase 3