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Blood, 1 June 2004, Vol. 103, No. 11, pp. 4243-4250.
Prepublished online as a Blood First Edition Paper on February 24, 2004; DOI 10.1182/blood-2003-08-2650.
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NEOPLASIA
Somatic inactivation of Nf1 in hematopoietic cells results in a progressive myeloproliferative disorder
Doan T. Le,
Namie Kong,
Yuan Zhu,
Jennifer O. Lauchle,
Abigail Aiyigari,
Benjamin S. Braun,
Endi Wang,
Scott C. Kogan,
Michelle M. Le Beau,
Luis Parada, and
Kevin M. Shannon
From the Department of Pediatrics, University of California, San Francisco, California; the Department of Laboratory Medicine, University of California, San Francisco, California; University of Texas Southwestern, Dallas, Texas; Section of Hematology/Oncology, Department of Medicine, and The Cancer Research Center, University of Chicago, Chicago, Illinois.
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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