β common receptor inactivation attenuates myeloproliferative disease in Nf1 mutant mice

• Published in: Blood Vol. 109; no. 4; pp. 1687 - 1691
• Main Authors: Kim, Andrew, Morgan, Kelly, Hasz, Diane E., Wiesner, Stephen M., Lauchle, Jennifer O., Geurts, Jennifer L., Diers, Miechaleen D., Le, Doan T., Kogan, Scott C., Parada, Luis F., Shannon, Kevin, Largaespada, David A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.02.2007; American Society of Hematology
• Series: Neoplasia
• Subjects: Animals; Disease Models, Animal; Hematopoietic Stem Cell Transplantation; Leukemia, Myelomonocytic, Chronic - etiology; Leukemia, Myelomonocytic, Chronic - prevention & control; Mice; Mice, Mutant Strains; Myeloproliferative Disorders - etiology; Myeloproliferative Disorders - prevention & control; Neoplasia; Neurofibromatosis 1 - genetics; Receptors, Granulocyte-Macrophage Colony-Stimulating Factor - genetics; Signal Transduction
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2006-05-025395

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.