[A case of acute promyelocytic leukemia with NUP98::RARG::LINE-L2a tripartite fusion and the mechanism of resistance to all-trans retinoic acid].

Abstract

This study reports a novel case of acute promyelocytic leukemia (APL) characterized by a tripartite fusion gene, NUP98::RARG::LINE-L2a, formed by the rearrangement of nucleoporin 98 (NUP98), retinoic acid receptor gamma (RARG), and long interspersed nuclear element L2a (LINE-L2a). The molecular mechanism underlying the patient's resistance to all-trans retinoic acid (ATRA) is also investigated. The 32-year-old male was admitted to Shandong Provincial Hospital Affiliated to Shandong First Medical University with complaints of "a 10-day cough and newly detected leukocytosis for one day". He was initially diagnosed with acute myeloid leukemia (AML) and bronchitis. Fundus hemorrhage was observed on physical examination. Coagulation tests showed elevated D-dimer and prolonged prothrombin time. Bone marrow smears showed 92% abnormal promyelocytes, and flow cytometry indicated an APL immunophenotype. However, the PML::RARA fusion gene formed by the promyelocytic leukemia (PML) gene and the retinoic acid receptor α gene (RARA) was negative by genetic testing, but identified by transcriptome sequencing as the NUP98:: RARG:: LINE-L2a tripartite fusion gene positive.. The patient responded poorly to ATRA-based induction therapy. Upon identifying the tripartite fusion gene, the treatment was switched to idarubicin combined with cytarabine chemotherapy. The patient achieved complete remission and subsequently underwent allogeneic hematopoietic stem cell transplantation. At the most recent follow-up of 16 months post-transplantation(May 2025), the patient remained in continuous remission. Sequence and fusion protein structural analyses revealed that the tripartite fusion leads to truncation of the ligand-binding domain of RARG gene, which is the key molecular mechanism underlying ATRA resistance.