Abstract
8p11 myeloproliferative syndrome (EMS) is a hematopoietic stem cell disorder characterized by myeloid hyperplasia and non-Hodgkin's lymphoma with chromosomal translocations fusing several genes, most commonly ZNF198, to fibroblast growth factor receptor-1 (FGFR1). However, patients with BCR-FGFR1 fusion present with typical chronic myeloid leukemia (CML). We demonstrate that ZNF198-FGFR1 induces EMS-like disease in mice, with myeloproliferation and T lymphoma arising from common multipotential progenitors. Mutation of FGFR1 Tyr766 attenuates both myeloid and lymphoid diseases, identifying phospholipase C-gamma1 as a downstream effector. Bcr-FGFR1 binds Grb2 via Bcr Tyr177 and induces CML-like leukemia in mice, whereas Bcr-FGFR1/Y177F lacks Grb2 binding and causes EMS-like disease. These results implicate different signaling pathways originating from both kinase and fusion partner in the pathogenesis of CML and EMS.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Animals
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Bone Marrow / metabolism
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Carrier Proteins / metabolism*
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Chromosome Breakage / genetics
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Chromosomes, Human, Pair 8 / genetics
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DNA-Binding Proteins / metabolism*
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GRB2 Adaptor Protein
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Humans
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Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
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Lymphoma, T-Cell / metabolism*
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Mice
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Myeloproliferative Disorders / metabolism*
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Oncogene Proteins / metabolism*
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Phospholipase C gamma
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Protein-Tyrosine Kinases*
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Proteins / metabolism
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Proto-Oncogene Proteins c-bcr
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Proto-Oncogene Proteins*
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Receptor Protein-Tyrosine Kinases / metabolism*
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Receptor, Fibroblast Growth Factor, Type 1
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Receptors, Fibroblast Growth Factor / metabolism*
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Signal Transduction
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Transcription Factors
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Translocation, Genetic / genetics
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Type C Phospholipases / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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DNA-Binding Proteins
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GRB2 Adaptor Protein
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GRB2 protein, human
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Grb2 protein, mouse
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Oncogene Proteins
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Proteins
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Proto-Oncogene Proteins
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Receptors, Fibroblast Growth Factor
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Transcription Factors
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ZMYM2 protein, human
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Zmym2 protein, mouse
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FGFR1 protein, human
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Fgfr1 protein, mouse
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Protein-Tyrosine Kinases
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Receptor Protein-Tyrosine Kinases
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Receptor, Fibroblast Growth Factor, Type 1
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BCR protein, human
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Bcr protein, mouse
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Proto-Oncogene Proteins c-bcr
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Type C Phospholipases
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Phospholipase C gamma