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 differentiation. If so, it is expected that overexpression of normal RAR alpha may perturb the RAR alpha/ RXR heterodimer formation and also the differentiation of myeloid cells. We have described here the morphology and the RA response of human RAR alpha cDNA transduced murine bone marrow cells using a retroviral vector. Most of RAR alpha transduced cells displayed promyelocyte like morphology and their proportion of c-kit expressing population was increased remarkably compared with the control (Neo(r) gene transduced cells). Furthermore, this morphology was observed even after these cells were brought into the semisolid culture containing IL-3 alone. Interestingly, immature RAR alpha transduced cells differentiated into mature granulocytes under the condition of the high concentration of RA(10(-6)M). We did not observe any effect of RAR alpha 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 promyelocytic leukemia bearing PML-RAR alpha translocation.