Acute promyelocytic leukemia (APL; FAB type M3)

Only 3 cases to date, 2 females aged 19 and 68 years (Yin et al., 2015; Shimomura et al., 2016) and a 37-years old male patient (Jovanovic et al., 2017).

The 68?year?old female presented with no disseminated intravascular coagulation (DIC) Bone marrow showed marked hypercellularity with 36.8% promyelocytes with azurophilic granules and Auer rods. Immunophenotyping was positive for CD33, CD34, CD64, CD117 and HLA?DR (Shimomura et al., 2016).

The 19-year-old woman received all-trans retinoic acid (ATRA), arsenic trioxide and gemtuzumab ozogamicin and achieved complete remission but relapsed 10 months later (Yin et al., 2015). The other female patient received induction therapy with ATRA in comination with chemotherapy. After initial resistance she achieved hematological remission after re?induction therapy and remained in hematological remission for more than a year when she developed relapse and died 1 years later (Shimomura et al., 2016). The male patient was commenced on ATRA as a single agent and showed response to therapy revealing maturation of the leukemic blasts in bone marrows taken at day 7 and day 16 that was associated with normalization of the platelet count. Because real-time quantitative PCR showed persistent high level IRF2BP2/RARA fusion transcripts with ATRA as a single agent, chemotherapy was added that resulted in ongoing remission 32 months from diagnosis (Jovanovic et al., 2017).

5 IRF2BP2 - 3 RARA.
In the case reported by Yin et al., 2015, breakpoints within IRF2BP2 exon 2 and RARA intron 2 were detected with breakpoints at positions 1687 bp in IRF2BP2 and 41620 bp in RARA. Through alternative splicing, 2 types of fusion transcripts between exon 1B of IRF2BP2 and exon 3 of RARA that resulted in an mRNA transcript 48 bp longer than variant 2 were found in a patient described by Shimomura et al., 2016. In the recently described case, fusion of exon 1 of IRF2BP2 to exon 3 of RARA was found (Jovanovic et al., 2017).

The N terminal part of the fusion protein originates from IRF2BP2 harbouring a zinc finger motif which may bind DNA and the C terminal part contains regions mediating DNA binding, ligand binding and RXR heterodimerization (Shimomura et al., 2015; Jovanovic et al., 2017).

The cryptic IRF2BP2/RARA fusion shows a similar breakpoint within the RARA gene as in PML-RARA and variant RARA fusions, thus retaining DNA binding, RXR heterodimerization, ligand binding, and co-repressor and co-activator interaction functions of RARA. The IRF2BP2/RARA fusion protein is likely the central leukemia-initiating event in APL patients by transforming hematopoietic stem/progenitor cells. In co-immunoprecipitation assays, IRF2BP2/RARA had the capacity to self-associate and behaved similarly to PML/RARA, inducing repression at retinoid response elements (Jovanovic et al., 2017).

IRF2BP2/RARA