E2a/Pbx1 Induces the Rapid Proliferation of Stem Cell Factor-Dependent Murine pro-T Cells That Cause Acute T-lymphoid or Myeloid Leukemias in Mice

Mol Cell Biol. 2004 Feb;24(3):1256-69. doi: 10.1128/mcb.24.3.1256-1269.2004.

Abstract

Oncoprotein E2a/Pbx1 is produced by the t(1;19) chromosomal translocation of human pre-B acute lymphoblastic leukemia. E2a/Pbx1 blocks differentiation of primary myeloid progenitors but, paradoxically, induces apoptosis in established pre-B-cell lines, and no transforming function of E2a/Pbx1 has been reported in cultured lymphoid progenitors. Here, we demonstrate that E2a/Pbx1 induces immortal proliferation of stem cell factor (SCF)-dependent pro-T thymocytes by a mechanism dependent upon both its transactivation and DNA-binding functions. E2a-Pbx1 cooperated with cytokines or activated signaling oncoproteins to induce cell division, as inactivation of conditional E2a/Pbx1 in either factor-dependent pro-T cells or pro-T cells made factor independent by expression of Bcr/Abl resulted in pro-T-cell quiescence, while reactivation of E2a/Pbx1 restored cell division. Infusion of E2a/Pbx1 pro-T cells in mice caused T lymphoblastic leukemia and, unexpectedly, acute myeloid leukemia. The acute lymphoblastic leukemia did not evidence further maturation, suggesting that E2a/Pbx1 establishes an early block in pro-T-cell development that cannot be overcome by marrow or thymic microenvironments. In an E2a/Pbx1 pro-T thymocyte clone that induced only pro-T acute lymphoblastic leukemia, coexpression of Bcr/Abl expanded its leukemic phenotype to include acute myeloid leukemia, suggesting that unique functions of cooperating signaling oncoproteins can influence the lymphoid versus myeloid character of E2a/Pbx1 leukemia and may cooperate with E2a/Pbx1 to dictate the pre-B-cell phenotype of human leukemia containing t(1;19).

Publication types

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

MeSH terms

  • Animals
  • Cell Division / physiology*
  • Co-Repressor Proteins
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Hematopoietic Stem Cells / metabolism
  • Homeodomain Proteins / metabolism*
  • Leukemia, Myeloid / etiology*
  • Leukemia, Myeloid / genetics
  • Lymphoid Enhancer-Binding Factor 1
  • Membrane Proteins / biosynthesis
  • Membrane Proteins / genetics
  • Mice
  • Nuclear Proteins / biosynthesis
  • Nuclear Proteins / genetics
  • Pre-B-Cell Leukemia Transcription Factor 1
  • Proto-Oncogene Proteins / metabolism*
  • Receptors, Notch
  • Repressor Proteins*
  • Stem Cell Factor / metabolism
  • Thymus Gland / metabolism
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*

Substances

  • Co-Repressor Proteins
  • DNA-Binding Proteins
  • Homeodomain Proteins
  • Lymphoid Enhancer-Binding Factor 1
  • Membrane Proteins
  • Nuclear Proteins
  • Pbx1 protein, mouse
  • Pre-B-Cell Leukemia Transcription Factor 1
  • Proto-Oncogene Proteins
  • Receptors, Notch
  • Repressor Proteins
  • Stem Cell Factor
  • Tle1 protein, mouse
  • Transcription Factors
  • pbx1 protein, human