PML-RARa action in acute promyelocytic leukemia

Acute promyelocytic leukemia is characterized by a translocation involving the retinoic acid receptor-alpha (RARa) locus on chromosome 17. In over 90 percent of cases, there is a balanced translocation t(15;17)(q24.1;q21.1) involving the ubiquitously expressed PML gene on chromosome 15, resulting in a PML-RARa fusion protein. As shown in the upper diagram, this PML-RARa fusion protein forms a homodimer that binds to RARa target genes and acts with corepressors to block transcription of these genes. This results in blocked differentiation and enhanced self-renewal of the promyelocytes. As shown in the lower diagram, the addition of all-trans retinoic acid (ATRA) and/or arsenic trioxide results in degradation of the PML-RARa fusion protein and release of the corepressors. This allows the normal RARa to bind to target genes and promote transcription leading to differentiation of the promyelocyte to a mature granulocyte.