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.
Le
Doan T
DT
Department of Pediatrics, University of California, San Francisco, 513 Parnassus Ave, HSE 302, San Francisco, CA 94143, USA.
Kong
Namie
N
Zhu
Yuan
Y
Lauchle
Jennifer O
JO
Aiyigari
Abigail
A
Braun
Benjamin S
BS
Wang
Endi
E
Kogan
Scott C
SC
Le Beau
Michelle M
MM
Parada
Luis
L
Shannon
Kevin M
KM
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