title: Clinical significance of productive immunoglobulin heavy chain gene rearrangements in childhood acute lymphoblastic leukemia.
abstract: We analyzed the CDR3 region of 80 children with B-cell acute lymphoblastic leukemia (B-ALL) using the ImMunoGeneTics Information System and JOINSOLVER. In total, 108 IGH@ rearrangements were analyzed. Most of them (75.3%) were non-productive. IGHV@ segments proximal to IGHD-IGHJ@ were preferentially rearranged (45.3%). Increased utilization of IGHV3 segments IGHV3-13 (11.3%) and IGHV3-15 (9.3%), IGHD3 (30.5%), and IGHJ4 (34%) was noted. In pro-B ALL more frequent were IGHV3-11 (33.3%) and IGHV6-1 (33.3%), IGHD2-21 (50%), IGHJ4 (50%), and IGHJ6 (50%) segments. Shorter CDR3 length was observed in IGHV@6, IGHD7, and IGHJ1 segments, whereas increased CDR3 length was related to IGHV3, IGHD2, and IGHJ4 segments. Increased risk of relapse was found in patients with productive sequences. Specifically, the relapse-free survival rate at 5 years in patients with productive sequences at diagnosis was 75% (standard error [SE] ±9%), whereas in patients with non-productive sequences it was 97% (SE ±1.92%) (p-value =0.0264). Monoclonality and oligoclonality were identified in 81.2% and 18.75% cases at diagnosis, respectively. Sequence analysis revealed IGHV@ to IGHDJ joining only in 6.6% cases with oligoclonality. The majority (75%) of relapsed patients had monoclonal IGH@ rearrangements. The preferential utilization of IGHV@ segments proximal to IGHDJ depended on their location on the IGHV@ locus. Molecular mechanisms occurring during IGH@ rearrangement might play an essential role in childhood ALL prognosis. In our study, the productivity of the rearranged sequences at diagnosis proved to be a significant prognostic factor.
authors.affiliation: Hematology/Oncology Unit, First Department of Pediatrics, University of Athens, Aghia Sophia' Children's Hospital, Athens, Greece. katharinakats@hotmail.com
authors.forename: Katerina
authors.initials: K
authors.lastname: Katsibardi
authors.forename: Maria
authors.initials: M
authors.lastname: Braoudaki
authors.forename: Chrissa
authors.initials: C
authors.lastname: Papathanasiou
authors.forename: Kalliopi
authors.initials: K
authors.lastname: Karamolegou
authors.forename: Fotini
authors.initials: F
authors.lastname: Tzortzatou-Stathopoulou
mesh_terms: D002648:Child; D002675:Child, Preschool; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007223:Infant; D053208:Kaplan-Meier Estimate; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D011379:Prognosis
chemical_list: D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region