Beta common receptor inactivation attenuates myeloproliferative disease in Nf1 mutant mice.
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.
Kim
Andrew
A
Department of Pediatrics, University of California San Francisco, USA.
Morgan
Kelly
K
Hasz
Diane E
DE
Wiesner
Stephen M
SM
Lauchle
Jennifer O
JO
Geurts
Jennifer L
JL
Diers
Miechaleen D
MD
Le
Doan T
DT
Kogan
Scott C
SC
Parada
Luis F
LF
Shannon
Kevin
K
Largaespada
David A
DA
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
D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor