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Blood, 15 February 2007, Vol. 109, No. 4, pp. 1687-1691.
Prepublished online as a Blood First Edition Paper on November 7, 2006; DOI 10.1182/blood-2006-05-025395.
 Previous Article | Next Article 
Submitted May 30, 2006
Accepted September 24, 2006
 common receptor inactivation attenuates
myeloproliferative disease in Nf1 mutant mice
Andrew Kim, Kelly Morgan, Diane E Hasz, Stephen M Wiesner, Jennifer O Lauchle, Jennifer L Geurts, Miechaleen D Diers, Doan T Le, Scott C Kogan, Luis F Parada, Kevin Shannon, and David A Largaespada*
Dept of Pediatrics, University of California San Francisco, CA
Dept of Genetics, Cell Biology & Development & Cancer Center, University of Minnesota, Minneapolis, MN
Dept of Laboratory Medicine, University of California San Francisco, CA
Center for Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX
Cancer Center, University of California San Francisco, CA
* Corresponding author; email: larga002{at}tc.umn.edu.
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 transplanted 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  chain (c) of the GM-CSF receptor. Mice reconstituted with Nf1-/-, -/- 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 hematopoieitc cells, concomitant loss of 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.
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