β 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, David A. Largaespada

Research output: Contribution to journalArticle

20 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)1687-1691
Number of pages5
JournalBlood
Volume109
Issue number4
DOIs
StatePublished - Feb 15 2007

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    Kim, A., Morgan, K., Hasz, D. E., Wiesner, S. M., Lauchle, J. O., Geurts, J. L., Diers, M. D., Le, D. T., Kogan, S. C., Parada, L. F., Shannon, K., & Largaespada, D. A. (2007). β common receptor inactivation attenuates myeloproliferative disease in Nf1 mutant mice. Blood, 109(4), 1687-1691. https://doi.org/10.1182/blood-2006-05-025395