CANCER

Partners in Repression

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Science  26 Jun 2009:
Vol. 324, Issue 5935, pp. 1621
DOI: 10.1126/science.324_1621c

Chromosomal translocations are structural abnormalities caused by the breaking and aberrant joining of regions from two or more chromosomes. If portions of two genes become fused, the fusion gene may encode a protein that combines two functions and produces a deleterious outcome. In some diseases, a single gene can be linked to one of several partners: Whereas the common gene dictates a basic similarity in disease etiology, the partner's identity may define a distinctive mechanism of causation.

In patients with acute promyelocytic leukemia (APL), the retinoic acid receptor alpha (RARA) is expressed as a fusion protein with one of five different partners, such as PML or PLZF. Although most APL patients express RARA-PML and can be treated with all-trans retinoic acid, those carrying RARA-PLZF are resistant.

Boukarabila et al. show that both fusion proteins inappropriately recruit the same Polycomb-repressive complex (PRC2) to mediate the silencing of retinoic acid–responsive genes. For RARA-PML, repression is reversed on treatment with retinoic acid; in contrast, RARA-PLZF also recruits PRC1, which contributes to tumorigenesis but is resistant to retinoic acid. Understanding the precise mechanisms of action of fusion proteins is important for the development of effective therapies.

Genes Dev. 23, 1195 (2009).

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