title: Mutations in epigenetic regulators are involved in acute lymphoblastic leukemia relapse following allogeneic hematopoietic stem cell transplantation.
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.
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.|Department of Hematology, Guangzhou General Hospital of Guangzhou Military Command (Guangzhou Liuhuaqiao Hospital), Guangzhou, PR China.
authors.forename: Haowen
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.
authors.forename: Li-Mengmeng
authors.initials: LM
authors.lastname: Wang
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Luo
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Lai
authors.affiliation: Center for Genetic and Genomic Analysis, Genesky Biotechnologies Inc., Shanghai, PR China.
authors.forename: Caihua
authors.initials: C
authors.lastname: Li
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.
authors.forename: Jimin
authors.initials: J
authors.lastname: Shi
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.
authors.forename: Yamin
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.
authors.forename: Shan
authors.initials: S
authors.lastname: Fu
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.
authors.forename: Yebo
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.
authors.forename: Ni
authors.initials: N
authors.lastname: Zhu
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.
authors.forename: Jingsong
authors.initials: J
authors.lastname: He
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.
authors.forename: Weiyan
authors.initials: W
authors.lastname: Zheng
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Yu
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Cai
authors.affiliation: Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, PR China.
authors.forename: He
authors.initials: H
authors.lastname: Huang
mesh_terms: D000328:Adult; D001483:Base Sequence; D002648:Child; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009154:Mutation / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000628:therapy*; D017422:Sequence Analysis, DNA; D014184:Transplantation, Homologous
keywords: acute lymphoblastic leukemia; allogeneic hematopoietic stem cell transplantation; epigenetic regulators; mutation; relapse