Yanmei Xu, Wentao Yang, Fangyi Yao, Zihao Wang, Jing Liu, Bo Huang, Xiaolin Li, Fangmin Zhong, Xiaozhong Wang

Jiangxi Province Key Laboratory of Immunology and Inflammation, Jiangxi Provincial Clinical Research Center for Laboratory Medicine, Department of Clinical Laboratory, The Second Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, People’s Republic of China

Correspondence: Xiaozhong Wang; Fangmin Zhong, Email wangxiaozhong@ncu.edu.cn; 1332721102@qq.com

Background: The occurrence and development of hematologic tumors are closely linked to cellular senescence. However, the molecular characteristics associated with this phenomenon in chronic myeloid leukemia (CML) have not been thoroughly investigated.
Methods: The cellular senescence score was calculated using gene set variation analysis. Consensus clustering algorithm was used to identify the molecular subtypes associated with cellular senescence. Clinical samples were collected for sequencing analysis to verify the expression of critical cellular senescence-related genes (CSRG). The effect of targeted inhibition of IGFBP2 on the malignant phenotype of CML-resistant cells was studied by cell experiments.
Results: The cellular senescence score in CML samples was significantly lower compared to normal samples. Higher expression of immune checkpoint markers correlated with increased cellular senescence scores. We identified two distinct molecular subtypes (C1 and C2) related to cellular senescence. The C1 subtype exhibited enhanced metabolic function and DNA damage repair capacity, while the C2 subtype showed higher infiltration of immune effector cells and activity in immune-related signaling pathways. We also discovered a group of drugs that displayed significant sensitivity differences between these two molecular subtypes, with the C2 subtype showing greater responsiveness to immunotherapy. Four critical cellular senescence-related genes (CSRGs), namely IGFBP2, IL7R, PLAU, and SUN1 demonstrated high diagnostic value for CML. We validated the expression levels of these four genes using clinical samples and confirmed through cell experiments that targeted inhibition of IGFBP2 effectively suppressed proliferation of resistant CML cells, promoted apoptosis, and enhanced therapeutic sensitivity to imatinib.
Conclusion: Our study conducted a comprehensive analysis on CSRG expression characteristics in CML and explored potential correlations between cellular senescence and immune function. The identification of molecular subtypes provides valuable insights into assessing individual patients’ biological characteristics for guiding clinical treatment decisions. Additionally, IGFBP2 has emerged as a promising therapeutic target for therapy-resistant cases of CML.

Keywords: chronic myeloid leukemia, cellular senescence, immune microenvironment, treatment, molecular subtype, diagnosis