Tie2-Cre-induced inactivation of a conditional mutant Nf1 allele in mouse results in a myeloproliferative disorder that models juvenile myelomonocytic leukemia.
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.
Gitler
Aaron D
AD
Department of Medicine, University of Pennsylvania Health System, Philadelphia, PA 19104, USA.
Kong
Yi
Y
Choi
John K
JK
Zhu
Yuan
Y
Pear
Warren S
WS
Epstein
Jonathan A
JA
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
D042787:Receptor, TIE-2; C045073:Cre recombinase; D019426:Integrases