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Abstract
The t(15;17)(q24;q21), generating a PML-RARA fusion gene, is the hallmark of acute promyelocytic leukemia (APL). At present, eight other genes fusing with RARA have been identified. The resulting fusion proteins retain domains of the RARA protein allowing binding to retinoic acid response elements (RARE) and dimerization with the retinoid X receptor protein (RXRA). They participate in protein-protein interactions, associating with RXRA to form hetero-oligomeric complexes that can bind to RARE. They have a dominant-negative effect on wild-type RARA/RXRA transcriptional activity. Moreover, RARA fusion proteins can homodimerize, conferring the ability to regulate an expanded repertoire of genes normally not affected by RARA. RARA fusion proteins behave as potent transcriptional repressors of retinoic acid signalling, inducing a differentiation blockage at the promyelocyte stage which can be overcome with therapeutic doses of ATRA or arsenic trioxide. However, resistance to these two drugs is a major problem, which necessitates development of new therapies.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
Key issues
Acute promyelocytic leukemia accounts for 10–15% of acute myeloid leukemia.
The promyelocytic leukemia–retinoic acid receptor α (RARA) chimeric gene, resulting from the t(15;17)(q24;q21), is identified in about 98% of the patients.
Eight other RARA partner genes have been identified in acute promyelocytic leukemia.
In all chimeric genes, the breakpoint occurs in intron 2 of the RARA gene.
All chimeric genes have a dominant-negative effect on wild-type RARA transcriptional activity.
All-trans retinoic acid and arsenic trioxide are very effective drugs but patients may be resistant or develop resistance.
Development of new therapies is much needed.