Molecular Characteristics and Clinical Significance of 12 Fusion Genes in Acute Promyelocytic Leukemia: A Systematic Review

Abstract

Acute promyelocytic leukemia (APL) is characterized by the generation of the promyelocytic leukemia-retinoic acid (RA) receptor α (PML-RARα) fusion gene. PML-RARα is the central leukemia-initiating event in APL and is directly targeted by all-trans-RA (ATRA) as well as arsenic. In classic APL harboring PML-RARα transcripts, more than 90% of patients can achieve complete remission when treated with ATRA combined with arsenic trioxide chemotherapy. In the last 20 years, more than 10 variant fusion genes have been found and identified in APL patients. These variant APL cases present different clinical phenotypes and treatment outcomes. All variant APL cases show a similar breakpoint within the RARα gene, whereas its partner genes are variable. These fusion proteins have the ability to repress rather than activate retinoic targets. These chimeric proteins also possess different molecular characteristics, thereby resulting in variable sensitivities to ATRA and clinical outcomes. In this review, we comprehensively analyze various rearrangements in variant APL cases that have been reported in the literature as well as the molecular characteristics and functions of the fusion proteins derived from different RARα partner genes and their clinical implications.

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].…”

Clinical and molecular features of acute promyelocytic leukemia with variant retinoid acid receptor fusions

“…Lijun Wen, 1* Yang Xu, 1* Li Yao, 1* Nana Wang, 1* Qinrong Wang, 1 Tianhui Liu, 2 Jinlan Pan, 1 Jiannong Cen, 1 Huifeng Zhou, 1 Miao Miao, 1 Yang W. Shao, 3,4,5 Xiaonan Wang, 5 Xiaoxia Wang, 5 Changgeng Ruan, 1 Depei Wu 1,2 and Suning Chen 1,2…”

Analysis of the oligomeric states of nucleophosmin using size exclusion chromatography

“…The overexpression of NPM1 has been observed in many types of solid tumors, including gastric 21 , prostate 22 , liver 23 and colon 24 . Translocation in the NPM1 gene has been reported for several hematopoietic malignancies 25 , 26 ; for example, t(2;5)(p23;q35) in 75% of anaplastic lymphoma kinase-positive anaplastic large cell lymphoma 27 , t(5;17)(q35;q31) in less than 1% of acute promyelocytic leukemia 28 , and t(3;5)(q25;q35) in less than 1% of acute myeloid leukemia (AML) 26 . Furthermore, approximately one-third of AML patients harbor frameshift mutations in exon 12 of the NPM1 gene 29 , resulting in the generation of a nuclear export signal in the C-terminal region of NPM1 and localization of the mutant NPM1 (NPM1c) to the cytoplasm.…”