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: Eva Chung, Chia-Lin Hsu, Motonari Kondo
• Journal: PloS one (PLoS One) Vol. 6 Issue 12 Pg. e28350 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 22164275 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Receptors, Notch
• Green Fluorescent Proteins
• MAP Kinase Kinase Kinases

Topics

• Animals
• Apoptosis
• Bone Marrow Transplantation
• Cell Differentiation
• Cell Separation
• Cell Survival
• Enzyme Activation
• Flow Cytometry
• Granulocytes (cytology)
• Green Fluorescent Proteins (metabolism)
• Hematopoietic Stem Cells (cytology)
• MAP Kinase Kinase Kinases (metabolism)
• MAP Kinase Signaling System
• Macrophages (cytology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Models, Biological
• Myeloproliferative Disorders (genetics, metabolism)
• Receptors, Notch (metabolism)