Acute promyelocytic leukemia: STATs, HATs, and HDACs

In this issue, both Dong and Tweardy (page 2637) and Maurer et al (page 2647) offer a detailed functional and biochemical characterization of the Stat5b-RARa fusion protein, which was originally described in a patient with acute promyelocytic leukemia (APL) several years ago (Arnould et al, Hum Mol Genetics. 1999;8:1741-1749). Stat5b is one of 5 genes that have now been identified as fusion partners of the retinoic acid receptor (RARa) in human APL, the others being PML (by far the most common), PLZF, NPM, and NuMA. Although alternative technical approaches likely account for some differences in the observations of these investigators, a number of take-home messages are clear and consistent. The Stat5b-RARa fusion protein blocks myeloid differentiation by inhibiting the transcriptional activity of the normal RARa. Moreover, it does so because, compared with the normal RARa, it is more efficient at recruiting transcriptional repressor complexes harboring histone deacetylases (HDACs) and less efficient at recruiting transcriptional coactivator complexes harboring histone acetylases (HATs). Both laboratories identified the coiled-coil domain within the Stat5b partner as the critical mediator of the Stat5b-RARa recruitment of the HDAC repressor complexes through its interaction with the SMRT corepressor. Although there is strong genetic evidence that the inhibition of normal PML activity by the PML-RARa fusion protein also contributes to the leukemic phenotype (Salomoni and Pandolfi, Cell. 2002;108:165170), the current investigators did not demonstrate any inhibition of Stat5 transcriptional activity by Stat5b-RARa. The generation of Stat5b-RARa is a rare event resulting from an interstitial chromosome 17 deletion rather than a chromosome translocation, which generates the other APL fusion proteins. Nevertheless, both these studies characterizing Stat5b-RARa fit the current paradigm that transcriptional repression is critical to the pathogenesis of certain types of human leukemia and offer further incentive for the development of rational drug therapy that can relieve this transcriptional repression by targeting HDACs or other members of the repressor complex. —Steven J. Collins Fred Hutchinson Cancer Research Center