Blood, 1 December 2001, Vol. 98, No. 12, pp. 3177-3178
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 D3
receptor. 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 (RAR
) was translocated in almost all cases of acute
promyelocyte leukemia (APL) lent further motivation to these studies.
In one form of APL the RAR is translocated and
subsequently fused to PLZF. Expression of this PLZF-RAR
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-RAR are
refractory to differentiation therapy.
Ward and colleagues (page 3290) have discovered a critical step in this
inhibition of differentiation by PLZF-RAR. They have found that
PLZF-RAR 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.
Robert Hromas
Indiana University Cancer Research
Institute
