Identification of a Novel Fusion Gene,IRF2BP2-RARA, in Acute Promyelocytic Leukemia

Abstract

Acute promyelocytic leukemia (APL) is characterized by fusion of RARA with PML, or rarely other gene partners. We report a patient with APL with a novel fusion between RARA and the interferon regulatory factor 2 binding protein 2 (IRF2BP2) genes. A 19-year-old woman presented with ecchymoses and epistaxis. Bone marrow examination showed morphologic and immunophenotypic features consistent with APL. PML oncogenic domain antibody was positive. Conventional cytogenetics, FISH, RT-PCR and oligonucleotide microarray for PML-RARA and common APL variant translocations were negative. Next generation RNAseq analysis followed by RT-PCR and direct sequencing revealed distinct breakpoints within IRF2BP2 exon 2 and RARA intron 2. The patient received ATRA, arsenic trioxide and gemtuzumab ozogamicin, and achieved complete molecular remission. However, the disease relapsed ten months later, two months after completion of consolidation therapy. This case expands the list of novel RARA partners identified in APL.

Down‐regulation of interferon regulatory factor 2 binding protein 2 suppresses gastric cancer progression by negatively regulating connective tissue growth factor

“…Koeppel et al have shown that IRF2BP2 is a transcriptional target of p53, promotes the proliferation of U2OS cells and accelerates cellular resistance to apoptosis induced by doxorubicin and actinomycin D treatment by inhibiting the p53‐mediated transactivation of the P21 and BAX genes. Whole transcriptome sequencing identified a novel IRF2BP2‐caudal type homeobox 1 fusion protein in mesenchymal chondrosarcoma and an IRF2BP2‐retinoic acid receptor alpha fusion protein in acute promyelocytic leukaemia . These studies suggest that IRF2BP2 may play a role in tumorigenesis and cancer progression.…”

“…IRF2BP2 has been reported to be involved in the malignancy of breast cancer, leukaemia and chondrosarcoma . The TCGA database revealed that the IRF2BP2 gene was amplified in most tumours, including GC.…”

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

“…Corresponding reciprocal fusion genes, RARα-PML , RARα-ZBTB16 , RARα-NPM , and RARα-FIP1L1 , are expressed and exist with the rest of the reciprocal fusion genes that have yet to be identified [7,8,9,30,65,72,76,85,98]. The reciprocal product potentially contains the N-terminal transactivation domain of the RARα protein that is linked to the C-terminal domains of the fusion partner.…”

“…To date, 11 variant fusion genes in APL, all involving the RARα gene, have been reported in a small percentage of APL cases. The partner genes include zinc finger and BTB domain-containing 16 ( ZBTB16 ; 11q23), nucleophosmin ( NPM ; 5q35), nuclear mitotic apparatus ( NuMA ; 11q13), signal transducer and activator of transcription (STAT) 5β ( STAT5b ; 17q21), protein kinase A (PKA) regulatory subunit type ( PRKAR1A ; 17q24), FIP1-like 1 ( FIP1L1 ; 4q12), BCL6 corepressor ( BCoR ; Xp11), oligonucleotide/oligosaccharide-binding fold-containing 2A ( OBFC2A ; 2q32) [6], transducin β-like 1 X-linked receptor 1 ( TBLR1 ; 3q26) [7], general transcription factor II-I ( GTF2I ; 7q11.23) [8], and interferon regulatory factor 2 binding protein 2 ( IRF2BP2 ; 1q42.3) [9]. The X-RARα (X:partner product) fusion pattern highlights the central role of RARα in the pathogenesis of APL.…”

“…The fusion gene involved exon 2 of the IRF2BP2 gene and intron 2 of the RARα gene. However, investigations on the molecular characteristics of this fusion gene are limited [9]. …”