Pumped on steroids

Steroid receptors play critical roles in myeloid development, functioning as transcriptional activators of the genes that guide the myeloid cell from progenitor to a mature granulocyte or monocyte. The 2 most important steroid receptors in myeloid development are the retinoic acid receptor and the related vitamin D₃receptor. Since the observation more than 2 decades ago that retinoic acid or vitamin D₃ could stimulate myeloid leukemia cell lines to differentiate to mature granulocytes or monocytes, the mechanism of action of these steroid receptors has been under intense study. The finding that the retinoic acid receptor alpha(RARα) was translocated in almost all cases of acute promyelocyte leukemia (APL) lent further motivation to these studies.

In one form of APL the RARα is translocated and subsequently fused to PLZF. Expression of this PLZF-RARα fusion protein is sufficient to block vitamin D₃ or retinoic acid–induced differentiation in myeloid leukemia cell lines. The mechanism of such inhibition of differentiation is critical to understanding how patients with APL caused by the PLZF-RARα are refractory to differentiation therapy.

Ward and colleagues (page 3290) have discovered a critical step in this inhibition of differentiation by PLZF-RARα. They have found that PLZF-RARα or PLZF alone binds to the vitamin D₃ receptor and blocks its ability to activate promoters that are important for myeloid development. According to their results, forced PLZF expression not only blocks morphologic and surface antigen changes associated with myeloid development but also inhibits transcription of the cell-cycle regulator p21, a known target of the vitamin D₃ receptor. Such p21 inhibition may also explain why APL cells with PLZF translocations continue to proliferate in the face of a differentiating stimulus. This study shows that the vitamin D₃ receptor may be responsible for establishing quiescence in the maturing myeloid cell. In addition, this study indicates that the vitamin D₃ receptor is an attractive target for neoplastic dominant negative point mutations, especially in monocytic leukemia.