2. Academic Validation
  3. Targeting DESI2 as a Novel Therapeutic Strategy for JAK2-Mutant Leukemias

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

  • Adv Sci (Weinh). 2025 Dec 3:e15127. doi: 10.1002/advs.202515127.
Husheng Mei 1,  Wuqiang Wen 2,  Wenjun Zhang 1,  Shujing Zhang 3,  Ting Sun 4,  Guiming Li 1,  Jing Zhang 4,  Shuang Qi 5,  Jie Zhou 1,  Bing Li 1,  Yunshuo Zhao 1,  Xiaotong Chen 1,  Bowen Li 1,  Yiying Xue 1,  Wang Lu 1,  Yanli Sun 6,  Jingyao Wang 7,  Hengyue Shan 7,  Shengzhe Zhang 8,  Yushan Huang 1,  Yisa Chen 1,  Wenchao Wang 5,  Qingsong Liu 5,  Wenchao Lu 6,  Li Tan 7,  Yi Ding 1,  Jianfei Fu 1,  Jun Long 1,  Lei Zhang 4,  Baobing Zhao 3,  Aibin Liang 1,  Baishan Jiang 2,  Jing Yang 1
Affiliations

Affiliations

  • 1 Department of Hematology, Tongji Hospital, Frontier Science Center for Stem Cell Research, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, P. R. China.
  • 2 Department of Radiation and Medical Oncology, Medical Research Institute, Frontier Science Center of Immunology and Metabolism, Hubei Key Laboratory of Tumor Biological Behavior, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, P. R. China.
  • 3 Key Lab of Chemical Biology, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, P. R. China.
  • 4 State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Tianjin & CAMS Key Laboratory of Gene Therapy for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, P. R. China.
  • 5 Anhui Province Key Laboratory of Medical Physics and Technology, Institute of Health and Medical Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, 230031, P. R. China.
  • 6 Lingang Laboratory, Shanghai, 200031, P. R. China.
  • 7 Interdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, 201210, P. R. China.
  • 8 Institute of Translational Medicine, Medical College, Yangzhou University, Yangzhou, 225001, P. R. China.
PMID: 41332324 DOI: 10.1002/advs.202515127
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.

Keywords

DESI2; JAK2‐V617F mutation; MPN; degrader; drug resistance.

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