Somatic inactivation of Nf1 in hematopoietic cells results in a progressive myeloproliferative disorder

DT Le, N Kong, Y Zhu, JO Lauchle, A Aiyigari… - Blood, 2004 - ashpublications.org
DT Le, N Kong, Y Zhu, JO Lauchle, A Aiyigari, BS Braun, E Wang, SC Kogan, MM Le Beau
Blood, 2004ashpublications.org
The NF1 tumor suppressor gene encodes a guanosine triphosphotase (GTPase)-activating
protein that negatively regulates Ras signaling and is inactivated in a subset of juvenile
myelomonocytic leukemias (JMMLs). Adoptive transfer of fetal liver cells from Nf1 mutant
mice models JMML; however, this system has important limitations as a platform for
performing biologic and preclinical studies. We have exploited the interferon-inducible Mx1-
Cre transgene to ablate a conditional mutant Nf1 allele in hematopoietic cells. Somatic …
Abstract
The NF1 tumor suppressor gene encodes a guanosine triphosphotase (GTPase)-activating protein that negatively regulates Ras signaling and is inactivated in a subset of juvenile myelomonocytic leukemias (JMMLs). Adoptive transfer of fetal liver cells from Nf1 mutant mice models JMML; however, this system has important limitations as a platform for performing biologic and preclinical studies. We have exploited the interferon-inducible Mx1-Cre transgene to ablate a conditional mutant Nf1 allele in hematopoietic cells. Somatic inactivation of Nf1 induces a myeloproliferative disorder with 100% penetrance that is associated with a sub-acute clinical course, tissue infiltration by myeloid cells, hypersensitivity to granulocyte-macrophage colony stimulating factor, hyperproliferation, and resistance to apoptosis. These Mx1-Cre, Nf1flox/flox mice establish a tractable experimental model for testing therapeutics and for identifying mutations that cooperate with hyperactive Ras in myeloid leukemogenesis. (Blood. 2004;103:4243-4250)
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