Objective Philadelphia(Ph)chromosome is the hallmark chromosome aberration in CML which confers the cancer phenotype of the disease.The Ph chromosome is present in more than 90%of CML patients,and almost all CML cases have the BCR-ABL fusion gene.Therapy drugs targeting the BCR-ABL tyrosine kinase have shown promising results in CML patients.However,the formation mechanism of the Ph chromosome and the genetic clonal evolution structure after targeted treatment are still unclear.This study aimed to investigate the genetic changes associated with CML relapse and to determine whether clonal evolution contributed to relapse.Methods In this study,We performed whole genome sequencing,basic bioinformatics analysis and clonal evolution analyses in a series of bone marrow specimens from a CML patient.Bone marrow biopsy specimens taken post-HSCT(BM-1),during the blast crisis phase(BM-2),and after complete remission(BM-3),as well as the patients skin biopsy(S-NC),were obtained.SNPs(single nucleotide polymorphisms)and INDELs(insertions and deletions)were detected using GATK,while CNVs(copy number variations)were identified by control-FREEC.Variation sites were annotated using ANNOVAR; somatic SNPs and INDELs were identified using muTect and Strelka; and somatic SVs(structure variations),including inter-chromosomal and intra-chromosomal translocations,deletions,and insertions,were identified using CREST.EXPANDS predicts the number of subpopulations(SPs)that coexist in a tumor,the size of the SPs in the tumor bulk,and the mutations that mark each SP.Results Point mutations,small INDELs,CNVs,and chromosome aberrations were detected in the bone marrow specimens and the skin tissue.More genetic aberrations were detected in the blast crisis phase sample.At the blast crisis phase,more than 400,000 new mutations arose,but almost all of them died out after Ph-targeted therapy.A series of missense mutations were on leukemia-related genes and DNA repair genes.BRIP1(BRCA1 interacting protein C-terminal helicase 1)is a DNA-dependent ATPase and helicase that interacts with BRCA1,which is required to maintain chromosomal stability.There is also a frame-shift deletion in the BRIP1 gene that involved in the DNA homologous recombination(HR)pathway in blast crisis phase and skin samples.EXPANDS predicted 4 SPs that coexisted in bone marrow samples BM-2 and BM-3.Conclusions The Ph chromosome is the “driver” clonal change in the original CML and the relapse.Both the patient and her sister had micro-deletions in the BCR gene region,however,the patient had a frame-shift BRIP1 mutation which may account for the malfunctioned homologous recombination DNA repair of the BCR gene region and the formation of Ph chromosome.The relapse of CML after HSCT was clearly from the patient,not from the donor.Our study explained why relapse happen in HSCT or organ transplantation patients.BRIP1 mutation caused Chromosome instabilities(CIN).CIN can be a driving force for cancer development.Mutations in DNA repair genes such as BRIP1 gene will lead to defects in DNA repair,resulting in an increase in genomic instability and malignant transformation of the cells,which may be the genetic basis for CML to form the Philadelphia chromosome.