Fyn is not essential for Bcr-Abl-induced leukemogenesis in mouse bone marrow transplantation models

Int J Hematol. 2012 Feb;95(2):167-75. doi: 10.1007/s12185-011-0994-5. Epub 2011 Dec 22.

Abstract

The Bcr-Abl oncogene causes human Philadelphia chromosome-positive (Ph(+)) leukemias, including B-cell acute lymphoblastic leukemia (B-ALL) and chronic myeloid leukemia (CML) with chronic phase (CML-CP) to blast crisis (CML-BC). Previous studies have demonstrated that Src family kinases are required for the induction of B-ALL, but not for CML, which is induced by Bcr-Abl in mice. In contrast, it has been reported that Fyn is up-regulated in human CML-BC compared with CML-CP, implicating Fyn in the blast crisis transition. Here, we aimed to delineate the exact role of Fyn in the induction/progression of Ph(+) leukemias. We found that Fyn is expressed in mouse hematopoietic cells at varying stages of development, including c-kit(+)Sca-1(+)Lin(-) cells. Notably, Fyn is highly expressed in some of human lymphomas, but not in human Ph(+) leukemias including CML-BC. In mouse bone marrow transplantation models, mice transplanted with wild-type or Fyn-deficient bone marrow cells transduced with Bcr-Abl showed no differences in the development of B-ALL or CML-like diseases. Similarly, Fyn deficiency failed to impact the development of myeloid CML-BC induced by Bcr-Abl and Hes1. Elevated expression of Fyn was not found in mouse samples of Bcr-Abl-mediated CML- and CML-BC-like diseases. Thus, Fyn is not required for the pathogenesis of Bcr-Abl-mediated leukemias.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Bone Marrow Transplantation
  • Disease Models, Animal
  • Fusion Proteins, bcr-abl / genetics*
  • Gene Expression Regulation, Leukemic / physiology*
  • Hematopoietic Stem Cells / physiology*
  • Homeodomain Proteins / genetics
  • Humans
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / physiopathology
  • Lymphoma, B-Cell / genetics
  • Lymphoma, B-Cell / physiopathology
  • Lymphoma, T-Cell / genetics
  • Lymphoma, T-Cell / physiopathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Myelodysplastic Syndromes / genetics
  • Myelodysplastic Syndromes / physiopathology
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / physiopathology
  • Proto-Oncogene Proteins c-fyn / genetics*
  • Proto-Oncogene Proteins c-fyn / physiology
  • Transcription Factor HES-1

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Hes1 protein, mouse
  • Homeodomain Proteins
  • Transcription Factor HES-1
  • FYN protein, human
  • Fusion Proteins, bcr-abl
  • Fyn protein, mouse
  • Proto-Oncogene Proteins c-fyn