OVEREXPRESSION OF RETINOIC ACID RECEPTOR-ALPHA SUPPRESSES MYELOID CELL-DIFFERENTIATION AT THE PROMYELOCYTE STAGE

Retinoic acid receptor (RAR) alpha is required to heterodimerize with retinoid X receptor (RXRs) in order to regulate myeloid differentiatio n. If so, it is expected that overexpression of normal RAR alpha may p erturb the RAR alpha/ RXR heterodimer formation and also the different iation of myeloid cells. We have described here the morphology and the RA response of human RAR alpha cDNA transduced murine bone marrow cel ls using a retroviral vector. Most of RAR alpha transduced cells displ ayed promyelocyte like morphology and their proportion of c-kit expres sing population was increased remarkably compared with the control (Ne o(r) gene transduced cells). Furthermore, this morphology was observed even after these cells were brought into the semisolid culture contai ning IL-3 alone. Interestingly, immature RAR alpha transduced cells di fferentiated into mature granulocytes under the condition of the high concentration of RA(10(-6)M). We did not observe any effect of RAR alp ha on monocytes. These results indicate that overexpression of normal RAR alpha is sufficient for inducing maturation arrest of myeloid cell lineage that is similar to the phenotype found in the acute promyeloc ytic leukemia bearing PML-RAR alpha translocation.