title: Tie2-Cre-induced inactivation of a conditional mutant Nf1 allele in mouse results in a myeloproliferative disorder that models juvenile myelomonocytic leukemia.
abstract: Neurofibromatosis type one (NF1) is a common genetic disorder affecting 1:4000 births and is characterized by benign and malignant tumors. Children with NF1 are predisposed to juvenile myelomonocytic leukemia. The Nf1 gene encodes neurofibromin, which can function as a Ras GTPase-activating protein. Neurofibromin deficiency in mice leads to mid-gestation lethality due to cardiovascular defects. We have previously shown that conditional inactivation of Nf1 using Tie2-Cre recapitulates the heart defects seen in Nf1(-/-) embryos. Tie2-Cre transgenic mice express Cre recombinase in all endothelial cells. Here, we show that Tie2-Cre-mediated deletion of Nf1 also leads to excision of Nf1 in the hematopoietic lineage. Surviving mice exhibit a myeloproliferative disorder similar to juvenile myelomonocytic leukemia seen in NF1 patients. These mice provide a useful model to study neurofibromin deficiency in hematopoiesis. Furthermore, defects in Tie2-Cre-expressing progenitors that result in heart and blood defects suggest that related heart and blood disorders in NF1 and other syndromes represent disorders of the hemangioblast.
authors.affiliation: Department of Medicine, University of Pennsylvania Health System, Philadelphia, PA 19104, USA.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: Gitler
authors.forename: Yi
authors.initials: Y
authors.lastname: Kong
authors.forename: John K
authors.initials: JK
authors.lastname: Choi
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhu
authors.forename: Warren S
authors.initials: WS
authors.lastname: Pear
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Epstein
mesh_terms: D000483:Alleles; D000818:Animals; D002648:Child; D004195:Disease Models, Animal; D020868:Gene Silencing; D016514:Genes, Neurofibromatosis 1; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000502:physiology; D006801:Humans; D019426:Integrases / Q000235:genetics / Q000378:metabolism*; D015477:Leukemia, Myelomonocytic, Chronic / Q000235:genetics / Q000503:physiopathology*; D007962:Leukocytes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000503:physiopathology*; D042787:Receptor, TIE-2 / Q000235:genetics / Q000378:metabolism*; D013154:Spleen / Q000166:cytology / Q000378:metabolism / Q000473:pathology
chemical_list: D042787:Receptor, TIE-2; C045073:Cre recombinase; D019426:Integrases