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.
Bibliographical noteFunding Information:
We would like to acknowledge the financial support from Natural Science Foundation of China (91845109, 21872169, 22109171, 22172190), Y.C. would like to acknowledge the support from the CAS Project for Young Scientists in Basic Research (YSBR-022) and the Young Cross Team Project of CAS (JCTD-2021-14). Z.C. would like to acknowledge the support from Jiangsu Planned Projects for Postdoctoral Researc Funds (2021K226B).