A bcr-3 isoform of RARα-PML potentiates the development of PML-RARα- driven acute promyelocytic leukemia

Jessica L. Pollock, Peter Westervelt, Arun K. Kurichety, Pier Giuseppe Pelicci, Jay L. Grisolano, Timothy J. Ley

Research output: Contribution to journalArticle

101 Scopus citations

Abstract

Acute promyelocytic leukemia (APML) most often is associated with the balanced reciprocal translocation t(15;17) (q22;q11.2) and the expression of both the PML-RARα and RARα-PML fusion cDNAs that are formed by this translocation. In this report, we investigated the biological role of a bcr-3 isoform of RARα-PML for the development of APML in a transgenic mouse model. Expression of RARα-PML alone in the early myeloid cells of transgenic mice did not alter myeloid development or cause APML, but its expression significantly increased the penetrance of APML in mice expressing a bcr-1 isoform of PML-RARα (15% of animals developed APML with PML-RARα alone vs. 57% with both transgenes, P < 0.001). The latency of APML development was not altered substantially by the expression of RARα-PML, suggesting that it does not behave as a classical 'second hit' for development of the disease. Leukemias that arose from doubly transgenic mice were less mature than those from PML-RARα transgenic mice, but they both responded to all-trans retinoic acid in vitro. These findings suggest that PML-RARα drives the development of APML and defines its basic phenotype, whereas RARα-PML potentiates this phenotype via mechanisms that are not yet understood.

Original languageEnglish
Pages (from-to)15103-15108
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume96
Issue number26
DOIs
StatePublished - Dec 21 1999

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