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

Abstract

Although acute promyelocytic leukemia (APL) is one of the most characterized forms of acute myeloid leukemia (AML), the molecular mechanisms involved in the development and progression of this disease are still a matter of study. APL is defined by the PML-RARA rearrangement as a consequence of the translocation t(15;17)(q24;q21). However, this abnormality alone is not able to trigger the whole leukemic phenotype and secondary cooperating events might contribute to APL pathogenesis. Additional somatic mutations are known to occur recurrently in several genes, such as FLT3, WT1, NRAS and KRAS, whereas mutations in other common AML genes are rarely detected, resulting in a different molecular profile compared to other AML subtypes. How this mutational spectrum, including point mutations in the PML-RARA fusion gene, could contribute to the 10%-15% of relapsed or resistant APL patients is still unknown. Moreover, due to the uncertain impact of additional mutations on prognosis, the identification of the APL-specific genetic lesion is still the only method recommended in the routine evaluation/screening at diagnosis and for minimal residual disease (MRD) assessment. However, the gene expression profile of genes, such as ID1, BAALC, ERG, and KMT2E, once combined with the molecular events, might improve future prognostic models, allowing us to predict clinical outcomes and to categorize APL patients in different risk subsets, as recently reported. In this review, we will focus on the molecular characterization of APL patients at diagnosis, relapse and resistance, in both children and adults. We will also describe different standardized molecular approaches to study MRD, including those recently developed. Finally, we will discuss how novel molecular findings can improve the management of this disease.

Keywords: APL; MRD; NGS; PML-RARA; acute promyelocytic leukemia; isoform; minimal residual disease; relapse; splicing.

Figure 1

Structure of the acute promyelocytic leukemia (APL) primary event: promyelocytic leukemia (PML) and retinoic acid receptor-α (RARA) proteins and the corresponding PML–RARA fusion protein with the breakpoint regions (marked in red) and hotspot mutations (in the box at the bottom of the figure; in black are presented commonly mutated positions, and in grey rarer changes). In PML: RING finger (R), B boxes (B1 and B2), coiled-coil domain (CC), nuclear localization signal (NLS), SUMO-interacting motif (SIM), and nuclear export signal (NES). In RARA: N-terminal domain (A, B), including the activation function domain 1 (AF-1), DNA-binding domain (C), hormone-binding domain (E) and other regulatory domains (D and F).

Figure 2

Acute promyelocytic leukemia (APL) molecular profile. APL and associated molecular events categorized by oncogenic mechanism. DNA mutations in genes involved with signaling pathways, chromatin organization, tumor suppressor and oncogenes, among others, and aberrantly expressed genes associated with PML-RARA rearrangement (in blue commonly mutated; in grey occasionally mutated).