In acute promyelocytic leukemia (APL), normal retinoid signaling is disrupted by an abnormal PML-RARα fusion oncoprotein, leading to a block in cell differentiation.
Further mechanistic studies show that CUDC-101 triggers caspase-dependent degradation of the promyelocytic leukemia-retinoic acid receptor alpha fusion protein.
The literature review indicated that allogeneic hematopoietic stem cell transplantation might be a therapeutic method to treat APL with IRF2BP2-RARA fusion.
In this article we laid emphasis on the rearrangement of the RARα gene and its different fusion partners resulting in variant forms of APL, their implication in underlying molecular pathogenesis of APL and also the different diagnostic modalities that should be employed for their rapid and accurate diagnosis.
Genetic mutations on PML-RARα in acute promyelocytic leukemia (APL) are reported to associate with arsenic trioxide (ATO) or all-trans retinoic acid (ATRA) resistance.
While most cases of APL harboring the PML/RARA fusion respond to all-trans retinoic acid (ATRA), some variant RARA rearrangements are ATRA insensitive.
Overcoming this differentiation arrest has the potential to improve the long-term survival of patients, as is the case in acute promyelocytic leukemia (APL), which is characterized by a chromosomal translocation involving the retinoic acid receptor alpha gene.
The outcome of acute promyelocytic leukemia (APL) has drastically improved following the identification of the PML-RARA oncogene as a key player in the pathogenesis of APL, and the subsequent introduction of all-trans retinoic acid (ATRA) as a therapeutic agent.
Promyelocytic leukemia-retinoic acid receptor α (PML-RARa) sets the cellular landscape of acute promyelocytic leukemia (APL) by repressing the transcription of RARa target genes and disrupting PML-NBs.
However, flourescence in situ hybridization (FISH) and reverse transcriptase polymerase chain reaction (RT-PCR) studies were negative for transcripts promyelocytic leukemia (<i>PML</i>) gene and retinoic acid receptor alpha (<i>RARA</i>) or <i>PML-RARA</i> fusion.
Herein, we for the first time report that phenylarsine oxide (PAO) could effectively induce PLZF-RARα variant fusion protein degradation through ubiquitin proteasome degradation pathway by apoptosis, which indicates that PAO might be a potential candidate for the treatment of PLZF-RARα variant APL.
APL is a model for oncogene-targeted therapies: <i>all-trans</i> retinoic acid (ATRA) and arsenic both target and degrade its ProMyelocytic Leukemia/Retinoic Acid Receptor α (PML/RARA) driver.
This is the first report proving that expression of HSP90 isomers are directly and differentially repressed by PML/RARA, with critical results on cellular homeostasis of target proteins, such as AKT, in APL blasts.
Once the diagnostic suspicion of acute promyelocytic leukemia (APL) has been raised, international guidelines recommend prompt initiation of tailored therapy and supportive care, while awaiting for genetic confirmation of the diagnosis, and the identification of the specific PML/RARA isoform by reverse transcriptase polymerase chain reaction (RT-PCR).
Influence of bcr-3 PML-RARα transcript on outcome in Acute Promyelocytic Leukemia patients of Kashmir treated with all-trans retinoic acid and/or arsenic tri-oxide.
The promyelocytic leukemia (PML)-retinoic acid receptor α (RARA) fusion is hypothesized to serve a vital role in the pathogenesis of acute promyelocytic leukemia (APL), which results from a reciprocal translocation between chromosomes 15 and 17, t(15;17)(q24;q21).
This is the case for Acute Promyelocytic Leukemias (APL) where SUMOylation, and subsequent destruction, of the PML-RARα fusion oncoprotein are triggered by arsenic trioxide, which is used as front-line therapy in combination with retinoic acid to cure APL patients.
Conversely, S100A3 knockdown in PML-RARα<sup>+</sup> APL and PML-RARα<sup>-</sup> AML cells reduces the amounts of RARα/PML-RARα and increases basal and ATRA-induced differentiation.
Arsenic trioxide (ATO) is another anti-cancer agent that promotes autophagy-dependent clearance of promyelocytic leukemiaretinoic acid receptor alpha gene (PML-RARα) in APL cells.