Pathogenetic implication of fusion genes in acute promyelocytic leukemia and their diagnostic utility

Abstract

Acute promyelocytic leukemia (APL) has been recognized as a discrete subset of hematopoietic malignancies constituting approximately 10% of acute myeloid leukemia cases. The hallmark reciprocal chromosomal translocation t(15;17) involving fusion between the retinoic acid receptor (RARα) gene and promyelocytic leukemia (PML) gene is a characteristic feature in APL which consequently results in the emergence of PML-RARα chimeric gene. This gene has been substantiated to be responsible for cellular transformation and is a prime target of all-trans-retinoic acid (ATRA) as well as arsenic-trioxide (ATO) therapy. Since this initial discovery, about 10 diverse translocation partner genes of RARα have been reported that result in variant APL forms strongly suggesting that disruption of RARα underlies its pathogenesis. The nature of the fusion partner has a significant bearing upon disease characteristics including sensitivity to retinoids and ATO and thereby underpins the need for rapid and accurate diagnosis and also demands a highly specific treatment approach. 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.

Classic and Variants APLs, as Viewed from a Therapy Response

“…Since the discovery of PML-RARA, more than a dozen diverse translocations involving RARA have been found in rare leukemia patients, often with typical morphological features of APL [57][58][59]. More recently, very rare fusions involving other retinoic acid receptors have also been described (Table 1, Figure 2) [60].…”

All-trans retinoic acid in non-promyelocytic acute myeloid leukemia: driver lesion dependent effects on leukemic stem cells

“…Notably, one of the first examples of a molecularly targeted anti-cancer drug, albeit discovered without knowledge about its mechanism of action, is all-trans retinoic acid (atRA). atRA has greatly improved the outcome of acute promyelocytic leukemia (APL), a subtype of AML characterized by expression of an aberrant retinoic acid receptor [45][46][47].…”

“…Acute promyelocytic leukemia (APL) is a subtype of AML that is characterized by rearrangements of the RARA gene. A number of different fusion partners have been described, but about 95% of cases harbor a t(15;17)(q22;q21), which fuses the promyelocytic leukemia (PML) gene to RARA [45,46,66]. The resulting PML-RARA fusion protein acts in a dominant negative manner on both the PML and RARA pathways, but the activity of both fusion partners is at least partially restored by pharmacological doses of atRA [45,66].…”

Acute Promyelocytic Leukemia: A Constellation of Molecular Events around a Single PML-RARA Fusion Gene

“…In roughly 1% to 2% of APL patients, novel translocations other than t(15;17) at either the cytogenetic or molecular level have been identified. To date, 12 molecular fusion variants of APL have been described, all involving the RARA gene [86] ( Table 2). The ZBTB16 (formerly PLZF)-RARA fusion, derived from the t(11;17)(q23;q21) rearrangement [87], has been reported in more than 30 patients, making it the most frequent APL molecular variant [85,86].…”

“…To date, 12 molecular fusion variants of APL have been described, all involving the RARA gene [86] ( Table 2). The ZBTB16 (formerly PLZF)-RARA fusion, derived from the t(11;17)(q23;q21) rearrangement [87], has been reported in more than 30 patients, making it the most frequent APL molecular variant [85,86]. Other reported translocations led to the rearrangement of RARA gene with NPM1 [88], NUMA1 [89], STAT5B [90], PRKAR1A [91], FIP1L1 [92], BCOR [93], NABP1 (formerly OBFC2A) [94], TBL1XR1 (formerly TBLR1) [95], GTF2I [96], IRF2BP2 [97], and FNDC3B [98].…”