Sun Shuzhang, Cheng Yixuan, Huang Xiange, Yan Yinjie, Hou Wanxin, Fang Houshun, Chen Yao, Ma Chunshuang, Lu Yiming, Zhou Zhiyi, Assaraf Yehuda G, Li Hui, Li Hegen, Xiao Ning
Institute of Traditional Chinese Medicine Surgery, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Department of Oncology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
Cell Death Dis. 2025 Sep 2;16(1):669. doi: 10.1038/s41419-025-07981-7.
Chemotherapy is the leading treatment for acute lymphoblastic leukemia (ALL). However, many ALL patients eventually develop relapses, the treatment of which remains a major challenge due to their chemoresistance phenotype. As a step towards this end, we here uncovered that relapsed ALL specimens exhibit a significantly lower expression of STAT6 but not of other STATs, when compared with their paired diagnosis specimens. Furthermore, STAT6 plays a distinctive role in chemosensitization of ALL cells to cytarabine (Ara-C), and T-box transcription factor 21 (TBX21) emerged as a plausible intrinsic biomarker of this Ara-C chemosensitization. We demonstrate that STAT6 undergoes SUMOylation on Lys-307 and sentrin/SUMO-specific protease 3 (SENP3)-mediated deSUMOylation in ALL cells. Most importantly, Ara-C specifically induced SENP3 expression and SENP3 knockdown sensitized ALL cells to Ara-C, with an impact equivalent to STAT6 knockout. These findings support the feedback resistance conferred upon ALL cells by Ara-C-induced SENP3 expression. Our findings uncover a novel role for STAT6 in ALL resistance to Ara-C and suggest that its targeted deprivation or pharmacological inhibition specifically sensitizes ALL cells to Ara-C, offering a plausible modality to surmount Ara-C resistance in future ALL treatment.
化疗是急性淋巴细胞白血病（ALL）的主要治疗方法。然而，许多ALL患者最终会复发，由于其化疗耐药表型，复发后的治疗仍然是一项重大挑战。为了朝着这个目标迈进，我们在此发现，与配对的诊断标本相比，复发ALL标本中STAT6的表达显著降低，但其他STATs的表达没有降低。此外，STAT6在ALL细胞对阿糖胞苷（Ara-C）的化疗增敏中发挥独特作用，并且T盒转录因子21（TBX21）成为这种Ara-C化疗增敏的一个合理的内在生物标志物。我们证明，在ALL细胞中，STAT6在赖氨酸307处发生SUMO化，并由sentrin/SUMO特异性蛋白酶3（SENP3）介导去SUMO化。最重要的是，Ara-C特异性诱导SENP3表达，而SENP3敲低使ALL细胞对Ara-C敏感，其影响等同于STAT6基因敲除。这些发现支持了Ara-C诱导的SENP3表达赋予ALL细胞的反馈抗性。我们的发现揭示了STAT6在ALL对Ara-C耐药中的新作用，并表明其靶向缺失或药理抑制可特异性使ALL细胞对Ara-C敏感，为未来ALL治疗中克服Ara-C耐药提供了一种可行的方式。
