Absence of terminal deoxynucleotidyl transferase expression in T‐ALL/LBL accumulates chromosomal abnormalities to induce drug resistance

Author:

Xiao Hui1,Wang Siqi1,Tang Yuejia1,Li Shanshan1,Jiang Yufeng1,Yang Yi1,Zhang Yinwen1,Han Yali1,Wu Xiaoyu1,Zheng Liang1,Li Yanxin1ORCID,Gao Yijin1

Affiliation:

1. Department of Hematology & Oncology, Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, School of Medicine Shanghai Jiao Tong University, National Health Committee Key Laboratory of Pediatric Hematology & Oncology Shanghai China

Abstract

AbstractT‐acute lymphoblastic leukemia/lymphoma (T‐ALL/LBL) is a malignant neoplasm of immature lymphoblasts. Terminal deoxynucleotidyl transferase (TDT) is a template‐independent DNA polymerase that plays an essential role in generating diversity for immunoglobulin genes. T‐ALL/LBL patients with TDT have a worse prognosis. However, how TDT promotes the disease progression of T‐ALL/LBL remains unknown. Here we analyzed the prognosis of T‐ALL/LBL patients in Shanghai Children's Medical Center (SCMC) and confirmed that TDT patients had a higher rate of recurrence and remission failure and worse outcomes. Cellular experiments demonstrated that TDT was involved in DNA damage repair. TDT knockout delayed DNA repair, arrested the cell cycle and decreased apoptosis to induce the accumulation of chromosomal abnormalities and tolerance to abnormal karyotypes. Our study demonstrated that the poor outcomes in TDT T‐ALL/LBL might be due to the drug resistance (VP16 and MTX) induced by chromosomal abnormalities. Our findings revealed novel functions and mechanisms of TDT in T‐ALL/LBL and supported that hematopoietic stem cell transplantation (HSCT) might be a better choice for these patients.

Funder

National Natural Science Foundation of China

Publisher

Wiley

Subject

Cancer Research,Oncology

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