Abstract
Acute B lymphoblastic leukemia (B-ALL) is one of the most common types of childhood cancer worldwide and chemotherapy is the main treatment approach. Despite good response rates to chemotherapy regiments, many patients eventually relapse and minimal residual disease (MRD) is the leading risk factor for relapse. The evolution of leukemic clones during disease development and treatment may have clinical significance. In this study, we performed immunoglobulin heavy chain (IGH) repertoire high throughput sequencing (HTS) on the diagnostic and post-treatment samples of 51 pediatric B-ALL patients. We identified leukemic IGH clones in 92.2% of the diagnostic samples and nearly half of the patients were polyclonal. About one-third of the leukemic clones have correct open reading frame in the complementarity determining region 3 (CDR3) of IGH, which demonstrates that the leukemic B cells were in the early developmental stage. We also demonstrated the higher sensitivity of HTS in MRD detection and investigated the clinical value of using peripheral blood in MRD detection and monitoring the clonal IGH evolution. In addition, we found leukemic clones were extensively undergoing continuous clonal IGH evolution by variable gene replacement. Dynamic frequency change and newly emerged evolved IGH clones were identified upon the pressure of chemotherapy. In summary, we confirmed the high sensitivity and universal applicability of HTS in MRD detection. We also reported the ubiquitous evolved IGH clones in B-ALL samples and their response to chemotherapy during treatment.
Highlights
Acute lymphoblastic leukemia (ALL) is one of the most common malignant disease in children worldwide and represents approximately a quarter of cancer diagnoses among children younger than 15 years
According to the disease risk stratification criteria, 19 of them were classified as Standard risk (SR), 18 as Intermediate risk (IR), and 14 as High risk (HR) (Table S1 in Supplementary Material, details in the section “Materials and Methods”)
Because B cell lineage ALL (B-ALL) is a kind of cancer originating from the immature stage of B cells, we investigated if the leukemic immunoglobulin heavy chain (IGH) rearrangements underwent positive selection
Summary
Acute lymphoblastic leukemia (ALL) is one of the most common malignant disease in children worldwide and represents approximately a quarter of cancer diagnoses among children younger than 15 years. With the improvement of treatment strategies, the 5-year survival rate of ALL has greatly increased from 57.2% during 1975–1977 to 91.8% during 2004–2010 according to the cancer statistics by National Institutes of Health (NIH). In spite of increased cure rates in pediatric ALL, relapse still occurs in approximately 15–20% of patients [2], and minimal residual disease (MRD) is the main risk factor for ALL relapse. It is important to consider increasing cure rates together with decreasing toxicity during treatment, and monitoring MRD can provide great help
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