Promyelocytic leukemia, a unique model to design treatments targeting oncogenes

All acute promyelocytic leukemia associated translocations involve a nuclea r receptor gene, RAR alpha. The most common translocation yields a PML/RAR alpha fusion protein.,PML/RARa homodimers with an increased affinity for co repressor proteins account for the block in myeloid differentiation. Interf erence of the fusion protein with PML function is likely responsible for pr oliferation of the leukemic cells, but the pathways involved are ill unders tood. Retinoic acid and arsenic both induce clinical remissions in patients . How exactly these drugs induce remissions is disputed, but both induce de gradation of the PML/RAR alpha fusion, retinoic acid targeting its RAR alph a moiety and arsenic its PML moiety. Transgenic mice have demonstrated that the reciprocal RAR alpha /PML fusion accelerates and facilitates leukemoge neisis. These animals constitute invaluable preclinical models to assess a variety of drugs targeted at the PML/RAR alpha fusion or acting downstream on its molecular targets.