title: Distinct stem cell myeloproliferative/T lymphoma syndromes induced by ZNF198-FGFR1 and BCR-FGFR1 fusion genes from 8p11 translocations.
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.
authors.affiliation: Children's Hospital, 330 Longwood Avenue, Boston, MA 02115, USA.
authors.forename: Sergei
authors.initials: S
authors.lastname: Roumiantsev
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Krause
authors.forename: Carola A
authors.initials: CA
authors.lastname: Neumann
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Dimitri
authors.forename: Frances
authors.initials: F
authors.lastname: Asiedu
authors.forename: Nicholas C P
authors.initials: NC
authors.lastname: Cross
authors.forename: Richard A
authors.initials: RA
authors.lastname: Van Etten
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D019457:Chromosome Breakage / Q000235:genetics; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000378:metabolism*; D051380:GRB2 Adaptor Protein; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism; D016399:Lymphoma, T-Cell / Q000378:metabolism*; D051379:Mice; D009196:Myeloproliferative Disorders / Q000378:metabolism*; D015513:Oncogene Proteins / Q000378:metabolism*; D051966:Phospholipase C gamma; D011505:Protein-Tyrosine Kinases; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D051562:Proto-Oncogene Proteins c-bcr; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors; D014178:Translocation, Genetic / Q000235:genetics; D010738:Type C Phospholipases / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; D015513:Oncogene Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D017468:Receptors, Fibroblast Growth Factor; D014157:Transcription Factors; C111777:ZMYM2 protein, human; C498438:Zmym2 protein, mouse; C496348:FGFR1 protein, human; C496349:Fgfr1 protein, mouse; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; C496613:BCR protein, human; C496614:Bcr protein, mouse; D051562:Proto-Oncogene Proteins c-bcr; D010738:Type C Phospholipases; D051966:Phospholipase C gamma