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Proc Natl Acad Sci U S A. 1999 Dec 21;96(26):15103-8.

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

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  • 1Washington University School of Medicine, Division of Bone Marrow Transplantation, Department of Internal Medicine, St. Louis, MO 63110, USA.

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-RARalpha and RARalpha-PML fusion cDNAs that are formed by this translocation. In this report, we investigated the biological role of a bcr-3 isoform of RARalpha-PML for the development of APML in a transgenic mouse model. Expression of RARalpha-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-RARalpha (15% of animals developed APML with PML-RARalpha alone vs. 57% with both transgenes, P < 0.001). The latency of APML development was not altered substantially by the expression of RARalpha-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-RARalpha transgenic mice, but they both responded to all-trans retinoic acid in vitro. These findings suggest that PML-RARalpha drives the development of APML and defines its basic phenotype, whereas RARalpha-PML potentiates this phenotype via mechanisms that are not yet understood.

PMID:
10611345
[PubMed - indexed for MEDLINE]
PMCID:
PMC24780
Free PMC Article

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