A global study for acute myeloid leukemia with RARG rearrangement

Abstract

Acute myeloid leukemia (AML) with RARG rearrangement has clinical, morphologic, and immunophenotypic features similar to classic acute promyelocytic leukemia. However, AML with RARG rearrangement is insensitive to all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) and carries a poor prognosis. We initiated a global cooperative study to define the clinicopathological features, genomic and transcriptomic landscape, and outcomes of AML with RARG rearrangements collected from 29 study groups/institutions worldwide. Thirty-four AML with RARG rearrangements were identified. Bleeding or ecchymosis was present at 18 (54.5%) patients. Morphology diagnosed as M3 and M3v accounted for 73.5% and 26.5% of cases, respectively. Immunophenotyping showed following characteristics: positive for CD33, CD13, and MPO but negative for CD38, CD11b, CD34, and HLA-DR. Cytogenetics showed normal karyotype in 38% and t(11;12) in 26% of patients. The partner genes of RARG were diverse and included CPSF6 (n=14), NUP98 (n=11), HNRNPc (n=6), HNRNPm (n=1), PML (n=1), and NPM1 (n=1). WT1- and NRAS/KRAS-mutations were common co-mutations. None of the 34 patients responded to ATRA and/or ATO. Death within 45 days from diagnosis occurred in 10 patients (~29%). At the last follow-up, 23 patients had died, and the estimated 2-year cumulative incidence of relapse, event-free survival, and overall survival were 68.7%, 26.7%, and 33.5%, respectively. Unsupervised hierarchical clustering using RNA-seq data from 201 AML patients showed that 81.8% of the RARG fusion samples clustered together, suggesting a new molecular subtype. RARG rearrangement is a novel entity of AML that confers a poor prognosis.

Retinoic acid receptor regulation of decision-making for cell differentiation

“…For nine acute promyelocytic patients, fusions have been described between RARγ and the genes for PML, NUP98, CPSF6 and NPM1, and these patients failed to respond to ATRA except for the one patient with the PML-RARγ fusion ( Conserva et al, 2019 ). A recent global study identified 34 patients with RARγ rearrangements, the partner genes were diverse, and the rearrangement conferred a poor prognosis ( Zhu et al, 2023 ).…”

Recurrent RARG trinary fusion and ligand binding domain truncation in variant acute promyelocytic leukemia resistant to retinoic acid but sensitive to homoharringtonine‐based therapy

“…reported previously. 1 Only three of them were children, manifesting adult-dominant characteristics. Paradoxically, all RARG-APL cases were clinically resistant to ATRA, but cells transfected with artificial NUP98::RARG fusion proteins were extremely sensitive to ATRA in vitro.…”

“…To date, eight partner genes of RARG (CPSF6, NUP98, PML, NPM1, HNRNPC, HNRNPM, SART3, and PRPF19) have been reported in vAPL, most of which were identified in adults. 1,[4][5][6] Among them, HNRNPC:: RARG fusion has been reported in two cases in detail. 7,8 The first reported HNRNPC::RARG positive vAPL case was a 43-year-old man resistant to ATRA and standard DA 3 + 7 regimen (daunorubicin and cytarabine).…”