Evidence of functional interaction between NuMA-RARα and RXRα in an in vivo model of acute promyelocytic leukemia

Abstract

Acute promyelocytic leukemia (APL) is characterized by reciprocal balanced chromosomal translocations involving retinoic acid receptor-α (RARα). RARα heterodimerizes with the retinoid X receptor-α (RXRα) and transcriptionally regulates myeloid differentiation in response to ATRA (all-trans retinoic acid). Several lines of evidence suggest that APL fusion proteins interact with RXRα. To elucidate the role of RXRα in APL, we conditionally knocked out RXRα in the hCG-NuMA-RARα APL mouse model. Phenotype analysis of NuMA-RARα+ mice demonstrated that these mice developed a myeloproliferative disease-like myeloid leukemia within 4 months of birth. While hemizygous and homozygous RXRα conditional knockout mice were phenotypically normal as late as 12 months of age, we observed that the leukemic phenotype in NuMA-RARα+ mice was dependent on the presence of functional RXRα. Bone marrow promyelocyte counts were significantly reduced in NuMA-RARα+ mice with RXRα knocked down. Significant differences in the accumulations of Gr-1+ and Mac-1+ cells were also seen. We further observed that genes previously identified to be cooperating events in APL were also regulated in an RXRα-dependent manner. We therefore propose that the APL fusion protein NuMA-RARα cooperates with RXRα in the development of leukemia in hCG-NuMA-RARα transgenic mice and suggest a novel role for RXRα in the pathogenesis of APL. © 2008 Macmillan Publishers Limited All rights reserved.