Oncotarget

Research Papers:

Mutations in epigenetic regulators are involved in acute lymphoblastic leukemia relapse following allogeneic hematopoietic stem cell transplantation

Haowen Xiao, Li-Mengmeng Wang, Yi Luo, Xiaoyu Lai, Caihua Li, Jimin Shi, Yamin Tan, Shan Fu, Yebo Wang, Ni Zhu, Jingsong He, Weiyan Zheng, Xiaohong Yu, Zhen Cai and He Huang _

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Oncotarget. 2016; 7:2696-2708. https://doi.org/10.18632/oncotarget.6259

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Abstract

Haowen Xiao1,2,*, Li-Mengmeng Wang1,*, Yi Luo1,*, Xiaoyu Lai1, Caihua Li3, Jimin Shi1, Yamin Tan1, Shan Fu1, Yebo Wang1, Ni Zhu1, Jingsong He1, Weiyan Zheng1, Xiaohong Yu1, Zhen Cai1, He Huang1

1Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, P R China

2Department of Hematology, Guangzhou General Hospital of Guangzhou Military Command (Guangzhou Liuhuaqiao Hospital), Guangzhou, P R China

3Center for Genetic and Genomic Analysis, Genesky Biotechnologies Inc., Shanghai, P R China

*These authors have contributed equally to this work

Correspondence to:

He Huang, e-mail: hehuangyu@126.com

Keywords: acute lymphoblastic leukemia, relapse, allogeneic hematopoietic stem cell transplantation, mutation, epigenetic regulators

Received: June 15, 2015     Accepted: October 23, 2015     Published: October 30, 2015

ABSTRACT

Although steady improvements to chemotherapeutic treatments has helped cure 80% of childhood acute lymphoblastic leukemia (ALL) cases, chemotherapy has proven to be less effective in treating the majority of adult patients, leaving allogeneic hematopoietic stem cell transplantation (allo-HSCT) as the primary adult treatment option. Nevertheless relapse are the leading cause of death following allo-HSCT. The genetic pathogenesis of relapse following allo-HSCT in Philadelphia chromosome- negative ALL (Ph ALL) remains unexplored. We performed longitudinal whole-exome sequencing analysis in three adult patients with Ph B-cell ALL (Ph B-ALL) on samples collected from diagnosis to relapse after allo-HSCT. Based on these data, we performed target gene sequencing on 23 selected genes in 58 adult patients undergoing allo-HSCT with Ph B-ALL. Our results revealed a significant enrichment of mutations in epigenetic regulators from relapsed samples, with recurrent somatic mutations in SETD2, CREBBP, KDM6A and NR3C1. The relapsed samples were also enriched in signaling factor mutations, including KRAS, PTPN21, MYC and USP54. Furthermore, we are the first to reveal the clonal evolution patterns during leukemia relapse after allo-HSCT. Cells present in relapsed specimens were genetically related to the diagnosed tumor, these cells therefore arose from either an existing subclone that was not eradicated by allo-HSCT therapy, or from the same progenitor that acquired new mutations. In some cases, however, it is possible that leukemia recurrence following allo-HSCT could result from a secondary malignancy with a distinct set of mutations. We identified novel genetic causes of leukemia relapse after allo-HSCT using the largest generated data set to date from adult patients with Ph B-ALL.


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