A PMLRARα transgene initiates murine acute promyelocytic leukemia

Diane Brown, Scott Kogan, Eric Lagasse, Irving Weissman, Myriam Alcalay, Pier Giuseppe Pelicci, Susan Atwater, J. Michael Bishop

Research output: Contribution to journalArticle

398 Citations (Scopus)

Abstract

The malignant cells of acute promyelocytic leukemia (APL) contain a reciprocal chromosomal translocation that fuses the promyelocytic leukemia gene (PML) with the retinoic acid receptor α gene (RARα). To test the hypothesis that the chimera PMLRARα plays a role in leukemogenesis, we expressed a PMLRARα cDNA in myeloid cells of transgenic mice. PMLRARα transgenic mice exhibited impaired neutrophil maturation early in life, which progressed at a low frequency over the course of several months to overt APL. Both the preleukemic state and the leukemia could be transplanted to nontransgenic mice, and the transplanted preleukemia could progress to APL. The APL recapitulated features of the human disease, including a response to retinoic acid. Retinoic acid caused the leukemic cells to differentiate in vitro and in vivo, eliciting remissions of both the preleukemic state and APL in mice. Our results demonstrate that PMLRARα impairs neutrophil differentiation and initiates the development of APL. The transgenic mice described here provide an apparently accurate model for human APL that includes clear evidence of tumor progression. The model should be useful for exploring the molecular pathogenesis of APL and the mechanisms of the therapeutic response to retinoic acid, as well as for preclinical studies of therapeutic regimens.

Original languageEnglish
Pages (from-to)2551-2556
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume94
Issue number6
DOIs
Publication statusPublished - Mar 18 1997

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Acute Promyelocytic Leukemia
Transgenes
Tretinoin
Transgenic Mice
Leukemia
Neutrophils
Preleukemia
Genetic Translocation
Retinoic Acid Receptors
Myeloid Cells
Genes
Complementary DNA
Therapeutics

Keywords

  • hematopoiesis
  • retinoic acid
  • t(15;17)
  • transgenic mice

ASJC Scopus subject areas

  • General
  • Genetics

Cite this

A PMLRARα transgene initiates murine acute promyelocytic leukemia. / Brown, Diane; Kogan, Scott; Lagasse, Eric; Weissman, Irving; Alcalay, Myriam; Pelicci, Pier Giuseppe; Atwater, Susan; Bishop, J. Michael.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 94, No. 6, 18.03.1997, p. 2551-2556.

Research output: Contribution to journalArticle

Brown, Diane ; Kogan, Scott ; Lagasse, Eric ; Weissman, Irving ; Alcalay, Myriam ; Pelicci, Pier Giuseppe ; Atwater, Susan ; Bishop, J. Michael. / A PMLRARα transgene initiates murine acute promyelocytic leukemia. In: Proceedings of the National Academy of Sciences of the United States of America. 1997 ; Vol. 94, No. 6. pp. 2551-2556.
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