The NR4A subfamily of orphan nuclear receptors (NR4A1, NR4A2, and NR4A3) function as nuclear transcription factors that transduce diverse extracellular and stress signals into altered gene transcription to coordinate apoptosis, proliferation, cell cycle arrest and DNA repair. We previously discovered that two of these receptors, NR4A1 and NR4A3, are potent tumor suppressors of acute myeloid leukemia (AML); they are silenced in human AML and abrogation of both genes in mice results in extremely rapid early postnatal development of AML.

To address the cellular and molecular mechanisms by which NR4As regulate myeloid homeostasis we have generated tamoxifen regulated conditional knockout mice to interrogate the preleukemic effects of NR4A1/3 deletion in hematopoietic cells. We show that deletion of NR4As in adult mice leads to development of transplantable AML disease with a mean survival latency of 15 weeks. Retroviral rescue of NR4A1 or NR4A3 expression after AML development is sufficient to prevent long-term reconstitution of leukemia initiating cells after transplantation into sub-lethally irradiated NOD-SCIDγ mice.

AML development in the conditional knockout mice is associated with loss of hematopoietic stem cell (HSC) homeostasis due to unscheduled HSC proliferation and abnormal skewing of the lineage development program of HSC subpopulations. Skewing of HSC developmental potential leads to a decrease in lymphoid-biased HSCs and relative overproduction of myeloid-biased HSCs, resulting in excessive generation of myeloid progenitor progeny. Our data indicate that NR4As are intrinsic transcriptional regulators of HSC homeostasis that are essential for coordination of lineage development programming of HSCs.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3387. doi:10.1158/1538-7445.AM2011-3387