title: Beta common receptor inactivation attenuates myeloproliferative disease in Nf1 mutant mice.
abstract: Neurofibromatosis type 1 (NF1) syndrome is caused by germline mutations in the NF1 tumor suppressor, which encodes neurofibromin, a GTPase activating protein for Ras. Children with NF1 are predisposed to juvenile myelomonocytic leukemia (JMML) and lethally irradiated mice given transplants with homozygous Nf1 mutant (Nf1-/-) hematopoietic stem cells develop a fatal myeloproliferative disorder (MPD) that models JMML. We investigated the requirement for signaling through the GM-CSF receptor to initiate and sustain this MPD by generating Nf1 mutant hematopoietic cells lacking the common beta chain (Beta c) of the GM-CSF receptor. Mice reconstituted with Nf1-/-, beta c-/- stem cells did not develop evidence of MPD despite the presence of increased number of immature hematopoietic progenitors in the bone marrow. Interestingly, when the Mx1-Cre transgene was used to inactivate a conditional Nf1 mutant allele in hematopoietic cells, concomitant loss of beta c-/- reduced the severity of the MPD, but did not abrogate it. Whereas inhibiting GM-CSF signaling may be of therapeutic benefit in JMML, our data also demonstrate aberrant proliferation of Nf1-/-myeloid progenitors that is independent of signaling through the GM-CSF receptor.
authors.affiliation: Department of Pediatrics, University of California San Francisco, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Kim
authors.forename: Kelly
authors.initials: K
authors.lastname: Morgan
authors.forename: Diane E
authors.initials: DE
authors.lastname: Hasz
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Wiesner
authors.forename: Jennifer O
authors.initials: JO
authors.lastname: Lauchle
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Geurts
authors.forename: Miechaleen D
authors.initials: MD
authors.lastname: Diers
authors.forename: Doan T
authors.initials: DT
authors.lastname: Le
authors.forename: Scott C
authors.initials: SC
authors.lastname: Kogan
authors.forename: Luis F
authors.initials: LF
authors.lastname: Parada
authors.forename: Kevin
authors.initials: K
authors.lastname: Shannon
authors.forename: David A
authors.initials: DA
authors.lastname: Largaespada
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018380:Hematopoietic Stem Cell Transplantation; D015477:Leukemia, Myelomonocytic, Chronic / Q000209:etiology* / Q000517:prevention & control; D051379:Mice; D008817:Mice, Mutant Strains; D009196:Myeloproliferative Disorders / Q000209:etiology* / Q000517:prevention & control; D009456:Neurofibromatosis 1 / Q000235:genetics*; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor