How retinoic acid and arsenic transformed acute promyelocytic leukemia therapy

Abstract

Acute promyelocytic leukemia (APL) is associated with a severe coagulopathy leading to rapid morbidity and mortality if left untreated. The definitive diagnosis of APL is made by identifying a balanced reciprocal translocation between chromosome 15 and 17. This t (15;17) results in a fusion transcript of the promyelocytic leukemia (PML) and retinoic acid receptor α (RARα) genes and expression of a functional PML/RARα protein. Detection of a fused PML/RARα genomic DNA sequence using florescent in-situ hybridization (FISH) or by detection of the PML/RARα fusion transcript via reverse transcriptase polymerase chain reaction (RT-PCR) has revolutionized the diagnosis and monitoring of APL. Once confirmed, APL is cured in over 90% of cases, making it the most curable subtype of acute leukemia today. Patients with low-risk APL are successfully treated using a chemotherapy-free combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO). In this review, we explore the work that has gone into the modern-day diagnosis and highly successful treatment of this once devastating leukemia.

Pharmaceutical/Clinical Strategies in the Treatment of Acute Promyelocytic Leukemia: All-Trans Retinoic Acid Encapsulation by Spray-Drying Technology as an Innovative Approach–Comprehensive Overview

“… Mechanisms of action of all-trans RA in the treatment of APL (adapted from [ 10 ]). Abbreviations: All-trans RA: all-trans retinoic acid; HAT: histone acetyl transferase; HD: Histone deacetylase; PML/RARA: fusion protein (oncoprotein); RARE: RA response elements.…”

“…Currently, it is considered the most curable subtype of AML with survival rates of 80% to 90%, with the combination of the all-trans-RA and arsenic trioxide (non-chemotherapy regimen) [ 8 , 9 ]. Eventually, the combination of these compounds and chemotherapy was also considered in the treatment of APL [ 7 , 9 , 10 , 11 ].…”

Retinoic acid receptors at 35: molecular convergence of vitamin A and steroid hormone action

“…Perhaps the most consequential point, in the aftermath of the discovery of RARα, was the subsequent finding that the balanced reciprocal translocation between chromosomes 15 and 17 causative of acute promyelocytic leukemia (APL) resulted in a fusion transcript between the promyelocytic leukemia (PML) and the RARA genes. Wilson Miller and Victoria Koros (Koros & Miller 2022) depict how this finding allowed for the detection of the PML/RARA fusion transcript thus revolutionizing the diagnosis and monitoring of APL. Astonishingly, >90% of the patients diagnosed with APL are cured with a combination of aT-RA and arsenic trioxide.…”

Gaillardin exerts potent antileukemic effects on HL‐60 cells and intensifies arsenic trioxide cytotoxicity: Providing new insight into sesquiterpene lactones in leukaemia treatment

“…The mutations and other destructive events categorize this malignancy into subtypes with varying prognoses 1 . In 1957, Leif Hillestad described a subtype of AML known as acute promyelocytic leukaemia (APL) 2 . One of the most prominent characteristics of APL is the presence of a balanced chromosomal translocation between chromosomes 15 and 17, which occurs in 95% of cases and causes differentiation arrest in the promyelocytic stage by forming the PML/RARα fusion protein 3 .…”