Abstract
Oncogenic mutations in components of cytokine signaling pathways elicit ligand-independent activation of downstream signaling, enhancing proliferation and survival in acute myeloid leukemia (AML). The myeloproliferative leukemia virus oncogene, MPL, a homodimeric receptor activated by thrombopoietin (THPO), is mutated in myeloproliferative disorders but rarely in AML. Here we show that wild-type MPL expression is increased in a fraction of human AML samples expressing RUNX1-ETO, a fusion protein created by chromosome translocation t(8;21), and that up-regulation of Mpl expression in mice induces AML when coexpressed with RUNX1-ETO. The leukemic cells are sensitive to THPO, activating survival and proliferative responses. Mpl expression is not regulated by RUNX1-ETO in mouse hematopoietic progenitors or leukemic cells. Moreover, we find that activation of PI3K/AKT but not ERK/MEK pathway is a critical mediator of the MPL-directed antiapoptotic function in leukemic cells. Hence, this study provides evidence that up-regulation of wild-type MPL levels promotes leukemia development and maintenance through activation of the PI3K/AKT axis, and suggests that inhibitors of this axis could be effective for treatment of MPL-positive AML.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Blotting, Western
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Bone Marrow / metabolism
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Bone Marrow / pathology
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Bone Marrow Transplantation
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Cell Cycle
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Cell Proliferation
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Chromosomes, Human, Pair 21 / genetics
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Chromosomes, Human, Pair 8 / genetics
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Core Binding Factor Alpha 2 Subunit / genetics
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Core Binding Factor Alpha 2 Subunit / metabolism*
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Humans
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Immunoenzyme Techniques
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Leukemia, Myeloid, Acute / genetics
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Leukemia, Myeloid, Acute / metabolism*
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Leukemia, Myeloid, Acute / pathology*
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Mice
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Molecular Sequence Data
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Oncogene Proteins, Fusion / genetics
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Oncogene Proteins, Fusion / metabolism*
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism*
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism*
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RNA, Messenger / genetics
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RUNX1 Translocation Partner 1 Protein
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Real-Time Polymerase Chain Reaction
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Receptors, Thrombopoietin / genetics
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Receptors, Thrombopoietin / metabolism*
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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Survival Rate
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Thrombopoietin / genetics
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Thrombopoietin / metabolism*
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Translocation, Genetic
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Tumor Cells, Cultured
Substances
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AML1-ETO fusion protein, human
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Core Binding Factor Alpha 2 Subunit
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Oncogene Proteins, Fusion
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RNA, Messenger
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RUNX1 Translocation Partner 1 Protein
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Receptors, Thrombopoietin
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MPL protein, human
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Thrombopoietin
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Phosphatidylinositol 3-Kinases
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Proto-Oncogene Proteins c-akt