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Translocations of the RARα gene in acute promyelocytic leukemia

Abstract

Acute promyelocytic leukemia (APL) has been recognized as a distinct clinical entity for over 40 years. Although relatively rare among hematopoietic malignancies (approximately 10% of AML cases), this disease has attracted a particularly good share of attention by becoming the first human cancer in which all-trans-retinoic acid (ATRA), a physiologically active derivative of vitamin A, was able to induce complete remission (CR). ATRA induced remission is not associated with rapid cell death, as in the case of conventional chemotherapy, but with a restoration of the ‘normal’ granulocytic differentiation pathway. With this remarkable medical success story APL has overnight become a paradigm for the differentiation therapy of cancer. A few years later, excitement with APL was further enhanced by the discovery that a cytogenetic marker for this disease, the t(15:17) reciprocal chromosomal translocation, involves a fusion between the retinoic acid receptor alpha (RARα) gene and a previously unknown locus named promyelocytic leukemia (PML). Consequence of this gene rearrangement is expression of the PML–RARα chimeric oncoprotein, which is responsible for the cellular transformation as well as ATRA response that is observed in APL. Since this initial discovery, a number of different translocation partner genes of RARα have been reported in rarer cases of APL, strongly suggesting that disruption of RARα underlies its pathogenesis. This article reviews various rearrangements of the RARα gene that have so far been described in literature, functions of the proteins encoded by the different RARα partner loci, and implications that these may have for the molecular pathogenesis of APL.

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Acknowledgements

We are grateful for support from the Leukaemia Research Fund of Great Britain (A Zelent), the Kay Kendall Leukaemia Fund (F Guidez), National Institutes of Health grants CA59936 (JD Licht, A Zelent, S Waxman) and KO8 CA73762 (A Melnick), as well as the American Cancer Society (JD Licht) and Samuel Waxman Cancer Research Foundation. JD Licht is a scholar of the Leukemia Society of America.

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Zelent, A., Guidez, F., Melnick, A. et al. Translocations of the RARα gene in acute promyelocytic leukemia. Oncogene 20, 7186–7203 (2001). https://doi.org/10.1038/sj.onc.1204766

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