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Variant Acute Promyelocytic Leukemia: Genetic Knowledge May Help to Guide Treatment

By: Lauren Harrison, MS
Posted: Monday, July 26, 2021

A team of researchers led by Jie Jin, MD, PhD, of Zhejiang University College of Medicine in Hangzhou, China, published an overview of the genetic landscape of variant acute promyelocytic leukemia (APL)—an aggressive type of acute myeloid leukemia (AML). Their work, published in Biomarker Research, offered an in-depth look at how the genetics of variant APL play into disease development and discussed treatment of variant APL.

Variant APL is typically considered in the differential when the phenotype of typical APL is present, but there is no translocation between chromosomes 15 and 17 (PML-RARA–negative). However, researchers found 16 other RARA rearrangements previously identified in variant APL. These RARA rearrangements seem to share similarities with PML-RARA in that they can form heterodimers or homodimers, recruit co-repressors, and have a negative effect on transcription of RARA. However, these rearrangements lack the target for arsenic trioxide (ATO), and only a fraction were sensitive to all-trans retinoic acid (ATRA), making treatment difficult.

In addition, researchers found reports of mutations in a variety of other genes reported to drive the APL phenotype (eg, RARB or RARG rearrangements as well as MLL and NPM1 rearrangements). The RARB rearrangement was able to form homodimers and could block neutrophil differentiation, but it was resistant to ATRA and ATO treatment. Many different RARG mutations have been identified; a majority were sensitive to AML therapy, and a smaller portion was sensitive to ATO and ATRA.

In clinical practice, it appears that variant APL is generally resistant to typical APL therapies, but chemotherapy seems to be an effective alternative. Thus, the authors suggested that when APL is diagnosed, confirmatory testing should be done to differentiate between variant and typical APL, so appropriate therapy can be started. The prognosis of variant APL is significantly inferior to typical APL.

Disclosure: The authors had no disclosures to report.



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