The pathophysiology of acute promyelocytic leukemia is most commonly due to a reciprocal translocation between chromosomes 15 and 17. The novel gene product causes a differentiation block in myeloid cells. There are multiple different binding partners for the RARA gene, so multiple translocations can contribute to the pathogenesis of acute promyelocytic leukemia.

• The pathophysiology of acute promyelocytic leukemia begins with a balanced reciprocal chromosomal translocation in hematopoietic stem cells.^[1]
• The chromosomal translocation involves the juxtaposition of the retinoic acid receptor– alpha gene (RARA) on the long arm of chromosome 17 with another gene, most commonly the promyelocytic leukemia gene (PML) on the long arm of chromosome 15. The translocation is designated as t(15;17)(q22;q12).^[2][3]
• The PML-RARA fusion product is a transcriptional regulator and binds to retinoic acid response elements in the promoter regions of the genome.
• The PML-RARA fusion product serves to recruit co-repressors of gene transcription, preventing myeloid differentiation.^[4][5]
• This is known as a differentiation block, since the cells are unable to differentiate into normal mature cells. The cells remain primitive and stem-like, which is the basis for the malignancy. The result of the chromosomal translocation is ineffective blood cell production and uncontrolled proliferation of malignant promyelocytes.^[2]
• In 95% of cases of acute promyelocytic leukemia, the translocation involved PML and RARA. However, it is important to note that RARA has multiple other binding partners which can lead to the development or acute promyelocytic leukemia, as shown in the table below.^[6]