Blood, 15 April 2002, Vol. 99, No. 8, pp. 2635-2635
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-RAR
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 (RAR) 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-RAR fusion protein blocks myeloid differentiation
by inhibiting the transcriptional activity of the normal
RAR. Moreover, it does so because, compared with the
normal RAR, 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-RAR 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-RAR fusion protein also contributes to the leukemic
phenotype (Salomoni and Pandolfi, Cell. 2002;108:165-170), the current
investigators did not demonstrate any inhibition of Stat5
transcriptional activity by Stat5b-RAR.
The generation of Stat5b-RAR 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-RAR 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
