TY - JOUR
T1 - β common receptor inactivation attenuates myeloproliferative disease in Nf1 mutant mice
AU - Kim, Andrew
AU - Morgan, Kelly
AU - Hasz, Diane E.
AU - Wiesner, Stephen M.
AU - Lauchle, Jennifer O.
AU - Geurts, Jennifer L.
AU - Diers, Miechaleen D.
AU - Le, Doan T.
AU - Kogan, Scott C.
AU - Parada, Luis F.
AU - Shannon, Kevin
AU - Largaespada, David A.
PY - 2007/2/15
Y1 - 2007/2/15
N2 - 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 β 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.
AB - 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 β 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.
UR - http://www.scopus.com/inward/record.url?scp=33846902274&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33846902274&partnerID=8YFLogxK
U2 - 10.1182/blood-2006-05-025395
DO - 10.1182/blood-2006-05-025395
M3 - Article
C2 - 17090653
AN - SCOPUS:33846902274
SN - 0006-4971
VL - 109
SP - 1687
EP - 1691
JO - Blood
JF - Blood
IS - 4
ER -