{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T04:30:41Z","timestamp":1789014641384,"version":"build-2803163510"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T00:00:00Z","timestamp":1681776000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005677","name":"Jos\u00e9 Carreras Leuk\u00e4mie-Stiftung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005677","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005677","name":"Jos\u00e9 Carreras Leuk\u00e4mie-Stiftung","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005677","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      The malignant transformation leading to a maturation arrest in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) occurs early in B-cell development, in a pro-B or pre-B cell, when somatic recombination of variable (V), diversity (D), and joining (J) segment immunoglobulin (IG) genes and the B-cell rescue mechanism of V\n                      <jats:sub>H<\/jats:sub>\n                      replacement might be ongoing or fully active, driving clonal evolution. In this study of newly diagnosed BCP-ALL, we sought to understand the mechanistic details of oligoclonal composition of the leukemia at diagnosis, clonal evolution during follow-up, and clonal distribution in different hematopoietic compartments.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Utilizing high-throughput sequencing assays and bespoke bioinformatics we identified BCP-ALL-derived clonally-related IGH sequences by their shared \u2018DNJ-stem\u2019.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We introduce the concept of \u2018marker DNJ-stem\u2019 to cover the entirety of, even lowly abundant, clonally-related family members. In a cohort of 280 adult patients with BCP-ALL, IGH clonal evolution at diagnosis was identified in one-third of patients. The phenomenon was linked to contemporaneous recombinant and editing activity driven by aberrant ongoing D\n                      <jats:sub>H<\/jats:sub>\n                      \/V\n                      <jats:sub>H<\/jats:sub>\n                      -DJ\n                      <jats:sub>H<\/jats:sub>\n                      recombination and V\n                      <jats:sub>H<\/jats:sub>\n                      replacement, and we share insights and examples for both. Furthermore, in a subset of 167 patients with molecular subtype allocation, high prevalence and high degree of clonal evolution driven by ongoing D\n                      <jats:sub>H<\/jats:sub>\n                      \/V\n                      <jats:sub>H<\/jats:sub>\n                      -DJ\n                      <jats:sub>H<\/jats:sub>\n                      recombination were associated with the presence of\n                      <jats:italic>KMT2A<\/jats:italic>\n                      gene rearrangements, while V\n                      <jats:sub>H<\/jats:sub>\n                      replacements occurred more frequently in Ph-like and DUX4 BCP-ALL. Analysis of 46 matched diagnostic bone marrow and peripheral blood samples showed a comparable clonal and clonotypic distribution in both hematopoietic compartments, but the clonotypic composition markedly changed in longitudinal follow-up analysis in select cases. Thus, finally, we present cases where the specific dynamics of clonal evolution have implications for both the initial marker identification and the MRD monitoring in follow-up samples.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>\n                      Consequently, we suggest to follow the marker DNJ-stem (capturing all family members) rather than specific clonotypes as the MRD target, as well as to follow both VDJ\n                      <jats:sub>H<\/jats:sub>\n                      and DJ\n                      <jats:sub>H<\/jats:sub>\n                      family members since their respective kinetics are not always parallel. Our study further highlights the intricacy, importance, and present and future challenges of IGH clonal evolution in BCP-ALL.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2023.1125017","type":"journal-article","created":{"date-parts":[[2023,4,18]],"date-time":"2023-04-18T01:45:00Z","timestamp":1681782300000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":11,"title":["Insights into IGH clonal evolution in BCP-ALL: frequency, mechanisms, associations, and diagnostic 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