<p>Acute Myeloid Leukemia with <em>NUP98-RARG</em> Gene Fusion Similar to Acute Promyelocytic Leukemia: Case Report and Literature Review</p>

Abstract

Retinoic acid receptor gamma (RARG) belongs to the nuclear receptor superfamily and has 90% homology to RAR alpha (RARA) and RAR beta. The promyelocytic leukemia (PML)-RARA fusion gene has been implicated in acute promyelocytic leukemia (APL). RARG gene rearrangement has been identified in a rare subtype of acute myeloid leukemia (AML) that resembles APL. To date, only 10 cases of gene rearrangements involving RARG (nucleoporin [NUP]98-RARG, promyelocytic leukemia protein-RARG, cleavage and polyadenylation-specific factor 6-RARG, or nucleophosmin [NPM]1-RARG-NPM1) have been reported. These patients show characteristics similar to APL, including bone marrow morphology, coagulation abnormality, and immunophenotype; however, they are resistant to all-trans retinoic acid and arsenic trioxide treatment. Moreover, there is no optimal therapeutic regimen for this subtype of AML. In this study, we report the clinical presentation and experimental findings of a case of AML with NUP98-RARG gene fusion similar to APL and review other cases of RARG gene rearrangement described in the literature.

Identification of a recurrent fusion NUP98–RARG in acute myeloid leukaemia resembling acute promyelocytic leukaemia

“…Two types of NUP98–RARG transcripts were identified. One was an in‐frame fusion, in which exon 12 of NUP98 (NM_016320.5) was fused to exon 4 of RARG (NM_000966.6) (Figure S1A ) , which was the same as previously reported 2,9–14 . The other one was an out‐of‐frame fusion, with exon 12 of NUP98 fused to exon 5 of RARG (Figure S1B ), which led to premature termination of the new fusion gene after 521 amino acids and destroyed the DBD and LBD domains of the RARG gene.…”

“…Till now, about 10 cases of NUP98 – RARG rearrangement have been reported. Review of the NUP98–RARG rearrangement showed they were associated patients who were all morphologically and immunophenotypically resembling APL, 2,9,12–14 except one case of AML‐M5 10 . The initiation of ATO and/or ATRA in case of NUP98 – RARA ‐negative leukaemia is not the satandard practice according to guidelines.…”

“…Most patients were insensitive to ATRA and/or ATO treatment compared with typical APL patients (Table 1 ) . Some of the patients showed sensitivity to an AML chemotherapy regimen 9,10,13–15 . However, most of these patients died within one year after diagnosis.…”

Current views on the genetic landscape and management of variant acute promyelocytic leukemia

“…In contrast to clinical finding, NUP98-RARG -postive APL was sensitive to ATRA treatment in murine system, which possibly was attributed to the different genetic backgrounds. Up to now, additional NUP98-RARG -positive APL patients have been reported by different groups including our group, and the breakpoint for NUP98-RARG was conserved, which located at NUP98 exon-12 and RARG exon-4 [ 100 – 104 ]. Though NUP98-RARG transformed murine HSPCs was sensitive to ATRA treatment ex vivo, all of NUP98-RARG -positive APL patients showed resistance to ATRA in clinic, and chemotherapy was required for their CR achievement.…”

Comment on Geoffroy, M.-C.; de Thé, H. Classic and Variants APLs, as Viewed from a Therapy Response. Cancers 2020, 12, 967

“…In fact, another patient with CPSF6-RARG has been reported in 2019 [ 3 ]. Since then, two more cases of CPSF6-RARG and two cases of NUP98-RARG have been reported [ 4 , 5 , 6 , 7 ]. Therefore, the number of reported patients has reached eight cases for CPSF6-RARG and six for NUP98-RARG .…”