Targeting DESI2 as a Novel Therapeutic Strategy for JAK2‐Mutant Leukemias

The JAK2-V617F mutation is the most common genetic alteration in myeloproliferative neoplasms (MPN), which can progress to secondary acute myeloid leukemia (sAML), a chemotherapy-resistant disease with limited treatment options and a poor prognosis. Although the JAK1/2 inhibitor Ruxolitinib is clinically approved, its efficacy is limited by toxicity to normal cells and the development of drug resistance. Here, the deSUMOylase DESI2 is identified as a novel component of the JAK2-V617F complex by mass spectrometry-based proteomics. Mechanistically, DESI2 selectively binds to and stabilizes JAK2-V617F by mediating its deSUMOylation and deubiquitination at lysine 962 (K962). Importantly, DESI2 protein is specifically and highly expressed in JAK2-mutant-driven cell lines and MPN primary clinical samples, suggesting its potential role in JAK2-V617F regulation and disease progression. Genetic depletion of DESI2 suppresses both JAK2 mutant cell growth and MPN disease onset in vitro and in vivo. Moreover, through a compound screen, followed by chemical proteomics and compound optimization, WWQ-03-012 is discovered, which selectively degrades mutant JAK2, induces primary leukemia cells death, and inhibits MPN progression through targeting DESI2 enzymatic activity in vitro and in vivo. These studies provide a novel therapeutic strategy against mutated JAK2 signaling in MPN and sAML.

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Publication Details

Journal
Advanced Science
Published
2025-12-03
DOI
https://doi.org/10.1002/advs.202515127
Primary Topic
Cytokine Signaling Pathways and Interactions
Type
article
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0.00
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article

Targeting DESI2 as a Novel Therapeutic Strategy for JAK2‐Mutant Leukemias

Xue Yan, Wenchao Lu, Jun Long, Jing Zhang et al.
Advanced Science
Cytokine Signaling Pathways and Interactions
article

Targeting DESI2 as a Novel Therapeutic Strategy for JAK2‐Mutant Leukemias

Xue Yan, Wenchao Lu, Jun Long, Jing Zhang, Wuqiang Wen, Jie Zhou, Yu‐Shan Huang, Yi Ding, Jianfei Fu, Aibin Liang, Shengzhe Zhang, Hengyue Shan, Baishan Jiang, Wenchao Wang, Wenjun Zhang, Yanli Sun, Y.B. Chen, Jing Yang, Baobing Zhao, Shuang Qi, Ting Sun, Yulong Zhao, Husheng Mei, Lu Wang, Jun Wang, Bowen Li, Guoliang Li, Li Tan, Bing Li, Xiaotong Chen, Lei Zhang, Shujing Zhang, Qingsong Liu
article en

Abstract

The JAK2-V617F mutation is the most common genetic alteration in myeloproliferative neoplasms (MPN), which can progress to secondary acute myeloid leukemia (sAML), a chemotherapy-resistant disease with limited treatment options and a poor prognosis. Although the JAK1/2 inhibitor Ruxolitinib is clinically approved, its efficacy is limited by toxicity to normal cells and the development of drug resistance. Here, the deSUMOylase DESI2 is identified as a novel component of the JAK2-V617F complex by mass spectrometry-based proteomics. Mechanistically, DESI2 selectively binds to and stabilizes JAK2-V617F by mediating its deSUMOylation and deubiquitination at lysine 962 (K962). Importantly, DESI2 protein is specifically and highly expressed in JAK2-mutant-driven cell lines and MPN primary clinical samples, suggesting its potential role in JAK2-V617F regulation and disease progression. Genetic depletion of DESI2 suppresses both JAK2 mutant cell growth and MPN disease onset in vitro and in vivo. Moreover, through a compound screen, followed by chemical proteomics and compound optimization, WWQ-03-012 is discovered, which selectively degrades mutant JAK2, induces primary leukemia cells death, and inhibits MPN progression through targeting DESI2 enzymatic activity in vitro and in vivo. These studies provide a novel therapeutic strategy against mutated JAK2 signaling in MPN and sAML.

Advanced ScienceVol. 13(7)
Linde (United States) (US), Tongji University (CN), Shandong University (CN), Chinese Academy of Sciences (CN), Chinese Academy of Medical Sciences & Peking Union Medical College (CN), Hefei Institutes of Physical Science (CN), Wuhan University (CN), Shanghai Institute of Organic Chemistry (CN), Zhongnan Hospital of Wuhan University (CN), Institute of Hematology & Blood Diseases Hospital (CN), Yangzhou University (CN)
Openalex Percentile: Top 47%
Cytokine Signaling Pathways and Interactions
DOIOpen Access PDFOpenAlex
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