Combination therapy based on venetoclax overcomes resistance to all-trans retinoic acid and arsenic trioxide in a variant acute promyelocytic leukemia with TNRC18::RARA fusion

Sep 29, 2026

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Correspondence describing a variant acute promyelocytic leukemia case harboring the TNRC18::RARA fusion. The PML::RARα fusion is common in APL, where ATRA and ATO usually yield high long-term survival, but variant RAR rearrangements often confer clinical resistance and worse prognosis. The reported patient showed insensitivity to ATRA and ATO yet achieved complete remission after venetoclax plus azacytidine. Transcriptome analysis further compared TNRC18::RARA with PML::RARA-positive APL and controls.

LanguageEnglish

CategoryHealthcare

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Correspondence

Background: PML::RARA in APL and resistance in variant RAR fusions

Case description: TNRC18::RARA variant APL and treatment response

Venetoclax rationale and prior evidence in APL

Transcriptome analysis (t-SNE, DEGs, GSEA)

Annals of Hematology (2025) 104:6467–6471 [https://doi.org/10.1007/s00277-025-06658-7](https://doi.org/10.1007/s00277-025-06658-7) CORRESPONDENCE Combination therapy based on venetoclax overcomes resistance to alltrans retinoic acid and arsenic trioxide in a variant acute promyelocytic leukemia with TNRC18::RARA fusion Wenjing Ding1,2 · Jun Zhao3 · Zheng Wang4 · Yongjing Liu5 · Man Wang2 · Hongjie Shen2 · Yun Chen3 · Jinyan Huang5 · Dong Li6 · Suning Chen2 · Lijun Wen2 Received: 13 June 2025 / Accepted: 22 September 2025 / Published online: 17 November 2025 © The Author(s) 2025 To the Editor, The PML::RARAfusion gene, resulting from the reciprocal chromosomal translocation t(15;17)(q22;q21), is detected in over 95% of acute promyelocytic leukemia(APL) patients. This aberration produces a fusion oncoprotein driven by the translocation. The combination therapy of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), has significantly improved outcomes, achieving long-term survival rate of up to 90% inAPL patients with PML::RARA fusion gene. Retinoic acid receptors (RARs), which belong to nuclear hormone receptors, regulate the transcription of target genes by binding to DNA elements. RARs consists of three isoforms: Wenjing Ding, Jun Zhao and Zheng Wang contributed equally to this work. 􀀍 Suning Chen[chensuning@sina.com](chensuning@sina.com) 􀀍 Lijun Wen [sudawlj@163.com](sudawlj@163.com) 1 Weifang People’s Hospital, Shandong Second Medical University, Weifang, P.R. China 2 Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, the First Affiliated Hospital of Soochow University, Soochow University, Shizi Street 188, Suzhou, PR 215006, P.R. China 3 Central Hospital Affiliated to Shandong First Medical University, Jinan, P.R. China 4 Suzhou Jsuniwell Medical Laboratory, Suzhou, P.R. China 5 Biomedical Big Data Center, the First Affiliated Hospital of Zhejiang University, Zhejiang University, Hangzhou, P.R. China 6 Nanjing BenQ Medical Center, the Affiliated BenQ Hospital of Nanjing Medical University, Nanjing, P.R. China retinoic acid receptor alpha (RARA), retinoic acid receptor beta (RARB) and retinoic acid receptor gamma (RARG) . With the recent widespread use of RNA sequencing (RNAseq) at diagnosis or relapse, an increasing number of cases with variant RAR rearrangements have been identified. These include 21 additional RARA rearrangements, two RARB rearrangements and 6 RARG rearrangements. In our department, we identified nine such variant APL cases from 2019 to 2022 (Fig. 1) . Although these variant RAR fusions retain domains similar to those of PML::RARA fusion gene, most confer clinical resistance toATRA and/orATO and are associated with poorer prognosis. In this study, we describe a case of APL harbouring TNRC18::RARA fusion gene resulting from the fusion of exon 5 ofTNRC18 to exon 3 of RARA, consistent with the breakpoint previously identified and repored by our group. The patient proved insensitivity to ATRA and ATO, but achieved complete remission following treatment with a combination of venetoclax and azacytidine. Venetoclax, a selective B-cell lymphoma 2 (BCL-2) inhibitor, is a small molecule that has been evaluated in several hematologic malignancies, both as monotherapy and in combination regimens. Although the combination of venetoclax with hypomethylating agents has demonstrated safety and efficacy in older or younger adults with newly diagnosed, ELN 2017 adverse-risk AML who are ineligible for intensive chemotherapy, there are only few reports of its use in the treatment of APL [1] . Using t-distributed stochastic neighbor embedding (t-SNE) analysis based on whole transcriptome sequencing data, we compared of the gene expression profile of this case with those of consecutive 35 PML::RARA-positive APL cases, 818 other AML cases, an

FAQs

Why are ATRA and arsenic trioxide often ineffective in variant APL with RAR rearrangements?

Variant RAR fusions retain domains similar to PML::RARA, but most confer clinical resistance to ATRA and/or ATO and are associated with poorer prognosis.

What treatment led to complete remission in the reported TNRC18::RARA case?

The patient achieved complete remission following treatment with a combination of venetoclax and azacytidine, despite insensitivity to ATRA and ATO.

What was compared in the gene expression analysis of TNRC18::RARA?

Whole-transcriptome sequencing data were used for t-SNE comparison between the TNRC18::RARA case and consecutive PML::RARA-positive APL cases, other AML cases, and healthy controls.

Sep 29, 2026

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