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PMID: 14729970 Published · ppublish English Journal Article Research Support, U.S. Gov't, Non-P.H.S. Research Support, U.S. Gov't, P.H.S.

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.

Molecular and cellular biology ·Vol. 24 ·No. 3 ·2004-02-00 ·Pages 1256-69

Sykes DB, Kamps MP

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).

MeSH Terms
Animals Cell Division/physiology Co-Repressor Proteins DNA-Binding Proteins/biosynthesis,genetics,metabolism Hematopoietic Stem Cells/metabolism Homeodomain Proteins/metabolism Leukemia, Myeloid/etiology,genetics Lymphoid Enhancer-Binding Factor 1 Membrane Proteins/biosynthesis,genetics Mice Nuclear Proteins/biosynthesis,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,genetics,metabolism
Chemicals
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
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Sykes David B
Department of Pathology, University of California-San Diego, La Jolla, California 92093-0612, USA.
Kamps Mark P
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.24.3.1256-1269.2004
Published
2004-02-00
Pages
1256-69
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC321418
Subset
IM
Grants
NCI NIH HHS · R01 CA056876 · United States
NCI NIH HHS · CA56876 · United States
External Links
PubMed source DOI: 10.1128/MCB.24.3.1256-1269.2004 PMC Full Text View journal details
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