Somatic inactivation of Nf1 in hematopoietic cells results in a progressive myeloproliferative disorder.
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, Nf1(flox/flox) mice establish a tractable experimental model for testing therapeutics and for identifying mutations that cooperate with hyperactive Ras in myeloid leukemogenesis.
Department of Pediatrics, University of California, San Francisco, 513 Parnassus Ave, HSE 302, San Francisco, CA 94143, USA.
Doan T
DT
Le
Namie
N
Kong
Yuan
Y
Zhu
Jennifer O
JO
Lauchle
Abigail
A
Aiyigari
Benjamin S
BS
Braun
Endi
E
Wang
Scott C
SC
Kogan
Michelle M
MM
Le Beau
Luis
L
Parada
Kevin M
KM
Shannon
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D002455:Cell Division / Q000276:immunology; D004195:Disease Models, Animal; D019204:GTP-Binding Proteins / Q000235:genetics; D019426:Integrases / Q000235:genetics; D007962:Leukocytes / Q000473:pathology / Q000502:physiology*; D007964:Leukocytosis / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009196:Myeloproliferative Disorders / Q000473:pathology / Q000503:physiopathology*; D064547:Myxovirus Resistance Proteins; D025542:Neurofibromin 1 / Q000235:genetics*; D015398:Signal Transduction / Q000276:immunology; D013163:Splenomegaly / Q000473:pathology / Q000503:physiopathology; D014764:Viral Proteins / Q000235:genetics; D018631:ras Proteins / Q000378:metabolism
C579070:Mx1 protein, mouse; D064547:Myxovirus Resistance Proteins; D025542:Neurofibromin 1; D014764:Viral Proteins; C045073:Cre recombinase; D019426:Integrases; D019204:GTP-Binding Proteins; D018631:ras Proteins