Current views on the genetic landscape and management of variant acute promyelocytic leukemia

Abstract

Acute promyelocytic leukemia (APL) is characterized by the accumulation of promyelocytes in bone marrow. More than 95% of patients with this disease belong to typical APL, which express PML-RARA and are sensitive to differentiation induction therapy containing all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), and they exhibit an excellent clinical outcome. Compared to typical APL, variant APL showed quite different aspects, and how to recognize, diagnose, and treat variant APL remained still challenged at present. Herein, we drew the genetic landscape of variant APL according to recent progresses, then discussed how they contributed to generate APL, and further shared our clinical experiences about variant APL treatment. In practice, when APL phenotype was exhibited but PML-RARA and t(15;17) were negative, variant APL needed to be considered, and fusion gene screen as well as RNA-sequencing should be displayed for making the diagnosis as soon as possible. Strikingly, we found that besides of RARA rearrangements, RARB or RARG rearrangements also generated the phenotype of APL. In addition, some MLL rearrangements, NPM1 rearrangements or others could also drove variant APL in absence of RARA/RARB/RARG rearrangements. These results indicated that one great heterogeneity existed in the genetics of variant APL. Among them, only NPM1-RARA, NUMA-RARA, FIP1L1-RARA, IRF2BP2-RARA, and TFG-RARA have been demonstrated to be sensitive to ATRA, so combined chemotherapy rather than differentiation induction therapy was the standard care for variant APL and these patients would benefit from the quick switch between them. If ATRA-sensitive RARA rearrangement was identified, ATRA could be added back for re-induction of differentiation. Through this review, we hoped to provide one integrated view on the genetic landscape of variant APL and helped to remove the barriers for managing this type of disease.

Atypical Rearrangements in APL-Like Acute Myeloid Leukemias: Molecular Characterization and Prognosis

“…APL is characterized by the t(15;17)(q24.1;q.2) balanced translocation, which results in the fusion of promyelocytic leukemia ( PML ) with retinoic acid receptor α ( RARA ) gene. This oncogene, found in 98% of cases, causes the transcriptional repression of RARA -targeted genes and the destruction of PML nuclear bodies (PML-NBs), resulting in altered self-renewal, senescence mechanisms, and response to DNA damage ( 3 – 7 ). With the introduction of daunorubicin in 1973, all-trans-retinoic acid (ATRA) in 1988, arsenic trioxide (ATO) in 1997, and, eventually, the chemo-free ATRA+ATO approach in 2006, the disease changed from highly fatal to curable leukemia in most cases ( 6 , 8 – 14 ).…”

“…About 2% of APL are characterized by atypical rearrangements, where the RARA is fused to partners other than PML or in which the translocation involves other members of the RAR superfamily ( Table 1 ) ( 6 ). These APL-like forms are a tough challenge for the clinician, both because of the difficulty of diagnosis and the generally unfavorable outcome due to diagnostic delays and to the frequent resistance of these forms to treatment commonly used for classical APL ( 3 , 4 , 101 , 102 ).…”

Clinical Response to Venetoclax and Decitabine in Acute Promyelocytic Leukemia With a Novel RARA-THRAP3 Fusion: A Case Report

“…To date, several other types of rare X-RARA fusions have been described. Unfortunately, most of the novel retinoic acid receptor fusions associated with APL are clinically resistant to ATRA or ATO (3,4).…”

A novel NUP98-JADE2 fusion in a patient with acute myeloid leukemia resembling acute promyelocytic leukemia

“… 1 In variant APL, RARA is fused with other partners, which dictate disease biology and treatment sensitivity. 2 Rarely, genomic rearrangements involving non- RARA genes have also been reported in patients with acute myeloid leukemia (AML) mimicking APL. 2-4 Although these findings suggest that alternative pathways may mediate the promyelocytic differentiation block, the underlying mechanisms have remained obscure.…”

“… 2 Rarely, genomic rearrangements involving non- RARA genes have also been reported in patients with acute myeloid leukemia (AML) mimicking APL. 2-4 Although these findings suggest that alternative pathways may mediate the promyelocytic differentiation block, the underlying mechanisms have remained obscure. The nucleoporin 98 ( NUP98 ) gene encoding a component of the nuclear pore complex is rearranged in various hematological malignancies associated with poor outcomes.…”