DNTT activation, TdT‐aided gene length mutation, and better prognosis in ATG‐based regimen allo‐HSCT in AML

Author:

Zhou Xiaosu1ORCID,Nie Daijing2ORCID,Zhang Yang12ORCID,Liu Zhixiu2,Zhao Yanli3ORCID,Zhang Jianping3,Wang Fang2,Fang Jiancheng2,Cao Panxiang2ORCID,Chen Xue12ORCID,Ma Xiaoli2ORCID,Yuan Lili2,Chen Jiaqi2ORCID,Tan Yincheng2,Chen Qihui4,Liu Ming2ORCID,Liu Mingyue5,Liu Yijun2,Wu Qisheng5,Lu Peihua136ORCID,Liu Hongxing1256ORCID

Affiliation:

1. Molecular Medicine Center Beijing Lu Daopei Institute of Hematology Beijing China

2. Division of Pathology & Laboratory Medicine Hebei Yanda Lu Daopei Hospital Langfang China

3. Department of Bone Marrow Transplantation Hebei Yanda Lu Daopei Hospital Langfang China

4. Department of Research and Development Beijing Geneprofile Technologies Co., Ltd Beijing China

5. Division of Pathology & Laboratory Medicine Beijing Lu Daopei Hospital Beijing China

6. Department of Oncology Capital Medical University Beijing China

Abstract

AbstractThis study aimed to investigate the relationship between anomalous DNA nucleotidylexotransferase (DNTT) activation and the mutagenesis of gene length mutations (LMs) in acute myeloid leukemia (AML), and the relevance of their prognosis in antithymocyte globulin (ATG)‐based regimen allogeneic hematopoietic stem cell transplantation (allo‐HSCT). A cohort of 578 AML cases was enrolled. Next‐generation sequencing was performed to screen mutations of 86 leukemia driver genes. RNA‐seq was used to analyze gene expression. Prognostic analysis was investigated in 239 AML cases who underwent ATG‐based regimen allo‐HSCT. We report a refined subtyping algorithm of LMs (type I–IV) based on sequence anatomy considering the TdT‐aided mutagenesis mechanism. GC content adjacent to LM junctions, inserted nontemplate nucleotide bases, and DNTT expression analysis supported the DNTT activation and TdT‐aided mutagenesis in type II/III LMs in the total AML cohort. Both single‐variate and multivariate analyses showed a better overall survival of FLT3 type III compared to type I in a subset of ATG‐based regimen allo‐HSCT cases. The novel LM subtyping algorithm not only deciphers the etiology of the mutagenesis of LMs but also helps to fine‐tune prognosis differentiation in AML. The possible prognostic versatility of this novel LM subtyping algorithm in terms of chemotherapy, targeted therapy, and allo‐HSCT merits further investigation.

Publisher

Wiley

Subject

Cancer Research,Molecular Biology

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