Oncogenic Role of RARG Rearrangements in Acute Myeloid Leukemia Resembling Acute Promyelocytic Leukemia

Overview

Journal Nat Commun

Date 2025 Jan 13

PMID 39805831

Authors

Feng Wang

Luyao Zhao

Yun Tan

Xufeng Cen

Huan Gao

Huimin Jiang

Ying Liu

Yunxuan Li

Tingting Zhang

Chenxi Zhao

Ting Shi

Guilin Xu

Churan Wang

Jiong Hu

Xia Li

Ya-Zhen Qin

Kankan Wang

Hong-Hu Zhu

Ke Li

Affiliations

Soon will be listed here.

Abstract

Acute myeloid leukemia (AML) featuring retinoic acid receptor-gamma (RARG) rearrangements exhibits morphological features resembling those of acute promyelocytic leukemia but is associated with drug resistance and poor clinical outcomes. However, the mechanisms underlying the role of RARG fusions in leukemogenesis remain elusive. Here, we show that RARG fusions disrupt myeloid differentiation and promote proliferation and self-renewal of hematopoietic stem and progenitor cells (HSPCs) by upregulating BCL2 and ATF3. RARG fusions overexpression leads to preleukemic phenotypes but fails to induce oncogenic transformation. However, the co-occurrence of RARG fusions and heterozygous Wt1 loss induce fully penetrant AML by activating MYC and HOXA9/MEIS1 targets. Leveraging Connectivity Map resources and high-throughput screening, we identify venetoclax, homoharringtonine, and daunorubicin as potential therapeutic options for RARG-AML. Overall, our findings provide pivotal insights into the molecular mechanisms governed by RARG fusions and enhanced by WT1 loss in AML development and propose a rational therapeutic strategy for RARG-AML.

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