Clonal Evolution Dissection Reveals High MSI2 Level Promotes Chemo-resistance in T-cell Acute Lymphoblastic Leukemia.

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive cancer with resistant clonal propagation in recurrence. We performed high-throughput droplet-based 5'-single-cell RNA with paired T-cell receptor (scTCR) sequencing of paired diagnosis-relapse (Dx_Rel) T-ALL samples to dissect the clonal diversities. Two leukemic evolutionary patterns, "clonal shift" and "clonal drift" were unveiled. Targeted single-cell DNA sequencing of paired Dx_Rel T-ALL samples further corroborated the existence of the two contrasting clonal evolution patterns, revealing that dynamic transcriptional variation might cause the mutationally static clones to evolve chemo-resistance. Analysis of commonly enriched drifted gene signatures showed expression of the RNA-binding protein MSI2 was significantly upregulated in the persistent TCR clonotypes at relapse. Integrated in vitro and in vivo functional studies suggested that MSI2 contributed to the proliferation of T-ALL and promoted chemo-resistance through the posttranscriptional regulation of MYC, pinpointing MSI2 as an informative biomarker and novel therapeutic target in T-ALL.

• Authors: Jingliao Zhang, Yongjuan Duan, Peng Wu, Yanxia Chang, Yue Wang, Tianyuan Hu, Chao Liu, Xiaoyan Chen, Suyu Zong, Xiaoli Chen, Yangping Wu, Linlin Jin, Yang Lan, Xiaoming Liu, Xuelian Cheng, Feng Ding, Tianyu Li, Xiaojuan Chen, Ye Guo, Yumei Chen, Wenyu Yang, Li Zhang, Yao Zou, Tao Cheng, Xiao-Fan Zhu, Yingchi Zhang
• Journal: Blood (Blood) (Oct 06 2023) ISSN: 1528-0020 [Electronic] United States
• PMID: 37801708 (Publication Type: Journal Article)
• Copyright: Copyright © 2023 American Society of Hematology.