Transformation of bone marrow B-cell progenitors by E2a-Hlf requires coexpression of Bcl-2

Mol Cell Biol. 2002 Nov;22(21):7678-87. doi: 10.1128/MCB.22.21.7678-7688.2002.

Abstract

The chimeric transcription factor E2a-Hlf is an oncoprotein associated with a subset of acute lymphoblastic leukemias of early B-lineage derivation. We employed a retroviral transduction-transplantation approach to evaluate the oncogenic effects of E2a-Hlf on murine B-cell progenitors harvested from adult bone marrow. Expression of E2a-Hlf induced short-lived clusters of primary hematopoietic cells but no long-term growth on preformed bone marrow stromal cell layers comprised of the AC6.21 cell line. Coexpression with Bcl-2, however, resulted in the sustained self-renewal of early preB-I cells that required stromal and interleukin-7 (IL-7) support for growth in vitro. Immortalized cells were unable to induce leukemias after transplantation into nonirradiated syngeneic hosts, unlike the leukemic properties and cytokine independence of preB-I cells transformed by p190(Bcr-Abl) under identical in vitro conditions. However, bone marrow cells expressing E2a-Hlf in combination with Bcl-2, but not E2a-Hlf alone, induced leukemias in irradiated recipients with long latencies, demonstrating both a requirement for suppression of apoptosis and the need for further secondary mutations in leukemia pathogenesis. Coexpression of IL-7 substituted for Bcl-2 to induce the in vitro growth of pre-B cells expressing E2a-Hlf, but leukemic conversion required additional abrogation of undefined stromal requirements and was associated with alterations in the Arf/Mdm2/p53 pathway. Thus, E2a-Hlf enhances the self-renewal of bone marrow B-cell progenitors without inciting a p53 tumor surveillance response or abrogating stromal and cytokine requirements for growth, which are nevertheless abrogated during progression to a leukemogenic phenotype.

Publication types

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

MeSH terms

  • Animals
  • B-Lymphocytes / cytology*
  • Basic-Leucine Zipper Transcription Factors
  • Blotting, Southern
  • Blotting, Western
  • Bone Marrow Cells / cytology
  • Bone Marrow Cells / metabolism
  • Cell Division
  • Cell Separation
  • Cell Transformation, Neoplastic*
  • DNA / metabolism
  • DNA-Binding Proteins / metabolism*
  • Disease Progression
  • Flow Cytometry
  • Genotype
  • Interleukin-7 / metabolism
  • Leukemia / etiology
  • Leukemia / metabolism
  • Methylcellulose / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Models, Genetic
  • Mutation
  • Oncogene Proteins, Fusion / metabolism*
  • Phenotype
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Retroviridae / genetics
  • Stem Cells / cytology*
  • Time Factors
  • Transgenes
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Basic-Leucine Zipper Transcription Factors
  • DNA-Binding Proteins
  • E2a-Hlf fusion protein, mouse
  • Interleukin-7
  • Oncogene Proteins, Fusion
  • Proto-Oncogene Proteins c-bcl-2
  • Tumor Suppressor Protein p53
  • Methylcellulose
  • DNA