title: Constitutive MAP kinase activation in hematopoietic stem cells induces a myeloproliferative disorder.
abstract: Myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPNs) are a group of myeloid neoplasms in which abnormal activation of the Ras signaling pathway is commonly observed. The PI3K/Akt pathway is a known target of Ras; however, activation of the PI3K/Akt pathway has been shown to lead to neoplastic transformation of not only myeloid but also lymphoid cells, suggesting that pathways other than the PI3K/Akt pathway should play a central role in pathogenesis of Ras-mediated MDS/MPN. The MEK/ERK pathway is another downstream target of Ras, which is involved in regulation of cell survival and proliferation. However, the role of the MEK/ERK pathway in the pathogenesis of MDS/MPN remains unclear. Here, we show that introduction of a constitutively activated form of MEK into hematopoietic stem cells (HSCs) causes hematopoietic neoplasms that are limited to MDS/MPNs, despite the multipotent differentiation potential of HSCs. Active MEK-mediated MDS/MPNs are lethal, but are not considered a frank leukemia because it cannot be transplanted into naïve animals. However, transplantation of MDS/MPNs co-expressing active MEK and an anti-apoptotic molecule, Bcl-2, results in T-cell acute lymphocytic leukemia (T-ALL), suggesting that longevity of cells may impact transplantability and alter disease phenotype. Our results clearly demonstrate the proto-oncogenic property of the MEK/ERK pathway in hematopoietic cells, which manifest in MDS/MPN development.
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: Eva
authors.initials: E
authors.lastname: Chung
authors.forename: Chia-Lin
authors.initials: CL
authors.lastname: Hsu
authors.forename: Motonari
authors.initials: M
authors.lastname: Kondo
mesh_terms: D000818:Animals; D017209:Apoptosis; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation; D002469:Cell Separation; D002470:Cell Survival; D004789:Enzyme Activation; D005434:Flow Cytometry; D006098:Granulocytes / Q000166:cytology; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009196:Myeloproliferative Disorders / Q000235:genetics / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism
chemical_list: D051880:Receptors, Notch; D049452:Green Fluorescent Proteins; D020930:MAP Kinase Kinase Kinases