Distinct stem cell myeloproliferative/T lymphoma syndromes induced by ZNF198-FGFR1 and BCR-FGFR1 fusion genes from 8p11 translocations

Cancer Cell. 2004 Mar;5(3):287-98. doi: 10.1016/s1535-6108(04)00053-4.

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

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Animals
  • Bone Marrow / metabolism
  • Carrier Proteins / metabolism*
  • Chromosome Breakage / genetics
  • Chromosomes, Human, Pair 8 / genetics
  • DNA-Binding Proteins / metabolism*
  • GRB2 Adaptor Protein
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism
  • Lymphoma, T-Cell / metabolism*
  • Mice
  • Myeloproliferative Disorders / metabolism*
  • Oncogene Proteins / metabolism*
  • Phospholipase C gamma
  • Protein-Tyrosine Kinases*
  • Proteins / metabolism
  • Proto-Oncogene Proteins c-bcr
  • Proto-Oncogene Proteins*
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptor, Fibroblast Growth Factor, Type 1
  • Receptors, Fibroblast Growth Factor / metabolism*
  • Signal Transduction
  • Transcription Factors
  • Translocation, Genetic / genetics
  • Type C Phospholipases / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • DNA-Binding Proteins
  • GRB2 Adaptor Protein
  • GRB2 protein, human
  • Grb2 protein, mouse
  • Oncogene Proteins
  • Proteins
  • Proto-Oncogene Proteins
  • Receptors, Fibroblast Growth Factor
  • Transcription Factors
  • ZMYM2 protein, human
  • Zmym2 protein, mouse
  • FGFR1 protein, human
  • Fgfr1 protein, mouse
  • Protein-Tyrosine Kinases
  • Receptor Protein-Tyrosine Kinases
  • Receptor, Fibroblast Growth Factor, Type 1
  • BCR protein, human
  • Bcr protein, mouse
  • Proto-Oncogene Proteins c-bcr
  • Type C Phospholipases
  • Phospholipase C gamma