Immunoglobulin Heavy Chain High-Throughput Sequencing in Pediatric B-Precursor Acute Lymphoblastic Leukemia: Is the Clonality of the Disease at Diagnosis Related to Its Prognosis?
Levy, Gabriel; Kicinski, Michal; Van der Straeten, Jonaet al.
BCP-ALL; clonal evolution analysis; high-throughput sequencing (HTS); minimal residual disease (MRD); prognostic factors; Pediatrics, Perinatology and Child Health
Abstract :
[en] High-throughput sequencing (HTS) of the immunoglobulin heavy chain (IgH) locus is a recent very efficient technique to monitor minimal residual disease of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). It also reveals the sequences of clonal rearrangements, therefore, the multiclonal structure, of BCP-ALL. In this study, we performed IgH HTS on the diagnostic bone marrow of 105 children treated between 2004 and 2008 in Belgium for BCP-ALL in the European Organization for Research and Treatment of Cancer (EORTC)-58951 clinical trial. Patients were included irrespectively of their outcome. We described the patterns of clonal complexity at diagnosis and investigated its association with patients' characteristics. Two indicators of clonal complexity were used, namely, the number of foster clones, described as clones with similar D-N2-J rearrangements but other V-rearrangement and N1-joining, and the maximum across all foster clones of the number of evolved clones from one foster clone. The maximum number of evolved clones was significantly higher in patients with t(12;21)/ETV6:RUNX1. A lower number of foster clones was associated with a higher risk group after prephase and t(12;21)/ETV6:RUNX1 genetic type. This study observes that clonal complexity as accessed by IgH HTS is linked to prognostic factors in childhood BCP-ALL, suggesting that it may be a useful diagnostic tool for BCP-ALL status and prognosis.
Disciplines :
Pediatrics Hematology Oncology
Author, co-author :
Levy, Gabriel; de Duve Institute, Université Catholique de Louvain, Brussels, Belgium ; Ludwig Institute for Cancer Research, Brussels, Belgium ; Department of Pediatric Oncology and Hematology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
Kicinski, Michal; European Organization for Research and Treatment of Cancer (EORTC) Headquarters, Brussels, Belgium
Van der Straeten, Jona; Molecular Hematology Laboratory, Vrije Universiteit Brussel, Universitair Ziekenhuis Brussel, Brussels, Belgium
Uyttebroeck, Anne; Department of Pediatric Hemato-Oncology, UZ Leuven, Leuven, Belgium
Ferster, Alina; Department of Pediatric Hematology-Oncology, Children's University Hospital Queen Fabiola, Université Libre de Bruxelles (ULB), Brussels, Belgium
De Moerloose, Barbara; Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, Ghent, Belgium
Dresse, Marie-Françoise ; Centre Hospitalier Universitaire de Liège - CHU > > Service de pédiatrie ; Department of Pediatrics, Centre Hospitalier Régional (CHR) de la Citadelle, Liège, Belgium
Chantrain, Christophe; Division of Pediatric Hematology-Oncology, Centre Hospitalier Chrétien (CHC) MontLégia, Liège, Belgium
Brichard, Bénédicte; Department of Pediatric Oncology and Hematology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium
Immunoglobulin Heavy Chain High-Throughput Sequencing in Pediatric B-Precursor Acute Lymphoblastic Leukemia: Is the Clonality of the Disease at Diagnosis Related to Its Prognosis?
This study was supported by a donation from the La Fondation contre le Cancer from Belgium and from Kom op tegen Kanker (Stand Up to Cancer) and the Flemish cancer society from Belgium. MB was supported by the Kinderkankerfonds (Belgium) and Télévie grant 28597737 (Belgium).
Hunger SP Mullighan CG. Acute lymphoblastic leukemia in children. N Engl J Med. (2015) 373:1541–52. 10.1056/NEJMra1400972 26465987
Howlader N Noone AM Krapcho M Miller D Brest A Yu M et al. SEER Cancer Statistics Review, 1975-2018. (2021). Available online at: https://seer.cancer.gov/csr/1975_2018/index.html (accessed November 16, 2021).
Gawad C Pepin F Carlton VEH Klinger M Logan AC Miklos DB et al. Massive evolution of the immunoglobulin heavy chain locus in children with B precursor acute lymphoblastic leukemia. Blood. (2012) 120:4407–17. 10.1182/blood-2012-05-429811 22932801
Pui C-H Campana D Evans WE. Childhood acute lymphoblastic leukaemia – current status and future perspectives. Lancet Oncol. (2001) 2:597–607. 10.1016/S1470-2045(01)00516-2
Pui C-H Relling MV Downing JR. Acute lymphoblastic leukemia. N Engl J Med. (2004) 350:1535–48. 10.1056/NEJMra023001 15071128
Lindqvist CM Lundmark A Nordlund J Freyhult E Ekman D Carlsson Almlöf J et al. Deep targeted sequencing in pediatric acute lymphoblastic leukemia unveils distinct mutational patterns between genetic subtypes and novel relapse-associated genes. Oncotarget. (2016) 7:64071–88. 10.18632/oncotarget.11773 27590521
Lefranc M-P Giudicelli V Ginestoux C Jabado-Michaloud J Folch G Bellahcene F et al. IMGT(R), the international ImMunoGeneTics information system(R). Nucleic Acids Res. (2009) 37:D1006–12. 10.1093/nar/gkn838 18978023
Cabaniols JP Fazilleau N Casrouge A Kourilsky P Kanellopoulos JM. Most alpha/beta T cell receptor diversity is due to terminal deoxynucleotidyl transferase. J Exp Med. (2001) 194:1385–90. 10.1084/jem.194.9.1385 11696602
Bashford-Rogers RJM Nicolaou KA Bartram J Goulden NJ Loizou L Koumas L et al. Eye on the B-ALL: B-cell receptor repertoires reveal persistence of numerous B-lymphoblastic leukemia subclones from diagnosis to relapse. Leukemia. (2016) 30:2312–21. 10.1038/leu.2016.142 27211266
Szczepañski T Willemse MJ Brinkhof B van Wering ER van der Burg M van Dongen JJ. Comparative analysis of Ig and TCR gene rearrangements at diagnosis and at relapse of childhood precursor-B–ALL provides improved strategies for selection of stable PCR targets for monitoring of minimal residual disease. Blood. (2002) 99:2315–23. 10.1182/blood.V99.7.2315 11895762
Steenbergen EJ Verhagen OJ van Leeuwen EF von dem Borne AE van der Schoot CE. Distinct ongoing Ig heavy chain rearrangement processes in childhood B-precursor acute lymphoblastic leukemia. Blood. (1993) 82:581–9. 8329713
van Dongen JJ Seriu T Panzer-Grümayer ER Biondi A Pongers-Willemse MJ Corral L et al. Prognostic value of minimal residual disease in acute lymphoblastic leukaemia in childhood. Lancet. (1998) 352:1731–8. 10.1016/S0140-6736(98)04058-6 34813082
Borowitz MJ Devidas M Hunger SP Bowman WP Carroll AJ Carroll WL et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia and its relationship to other prognostic factors: a children’s oncology group study. Blood. (2008) 111:5477–85. 10.1182/blood-2008-01-132837 18388178
Borowitz MJ Wood BL Devidas M Loh ML Raetz EA Salzer WL et al. Prognostic significance of minimal residual disease in high risk B-ALL: a report from children’s oncology group study AALL0232. Blood. (2015) 126:964–71. 10.1182/blood-2015-03-633685 26124497
Cavé H van der Werff ten Bosch J Suciu S Guidal C Waterkeyn C Otten J et al. Clinical significance of minimal residual disease in childhood acute lymphoblastic leukemia. European organization for research and treatment of cancer–childhood leukemia cooperative group. N Engl J Med. (1998) 339:591–8. 10.1056/NEJM199808273390904 9718378
van Dongen JJ van der Velden VH Brüggemann M Orfao A. Minimal residual disease diagnostics in acute lymphoblastic leukemia: need for sensitive, fast, and standardized technologies. Blood. (2015) 125:3996–4009. 10.1182/blood-2015-03-580027 25999452
Faham M Zheng J Moorhead M Carlton VEH Stow P Coustan-Smith E et al. Deep-sequencing approach for minimal residual disease detection in acute lymphoblastic leukemia. Blood. (2012) 120:5173–80. 10.1182/blood-2012-07-444042 23074282
Kotrova M Trka J Kneba M Brüggemann M. Is next-generation sequencing the way to go for residual disease monitoring in acute lymphoblastic leukemia? Mol Diagn Ther. (2017) 21:481–92. 10.1007/s40291-017-0277-9 28452038
Germano G del Giudice L Palatron S Giarin E Cazzaniga G Biondi A et al. Clonality profile in relapsed precursor-B-ALL children by GeneScan and sequencing analyses. Consequences on minimal residual disease monitoring. Leukemia. (2003) 17:1573–82. 10.1038/sj.leu.2403008 12886245
Kotrova M Muzikova K Mejstrikova E Novakova M Bakardjieva-Mihaylova V Fiser K et al. The predictive strength of next-generation sequencing MRD detection for relapse compared with current methods in childhood ALL. Blood. (2015) 126:1045–7. 10.1182/blood-2015-07-655159 26294720
Ferret Y Caillault A Sebda S Duez M Grardel N Duployez N et al. Multi-loci diagnosis of acute lymphoblastic leukaemia with high-throughput sequencing and bioinformatics analysis. Br J Haematol. (2016) 173:413–20. 10.1111/bjh.13981 26898266
Pulsipher MA Carlson C Langholz B Wall DA Schultz KR Bunin N et al. IgH-V(D)J NGS-MRD measurement pre- and early post-allotransplant defines very low- and very high-risk ALL patients. Blood. (2015) 125:3501–8. 10.1182/blood-2014-12-615757 25862561
Brüggemann M Kotrová M Knecht H Bartram J Boudjogrha M Bystry V et al. Standardized next-generation sequencing of immunoglobulin and T-cell receptor gene recombinations for MRD marker identification in acute lymphoblastic leukaemia; a EuroClonality-NGS validation study. Leukemia. (2019) 33:2241–53. 10.1038/s41375-019-0496-7 31243313
Logan AC Vashi N Faham M Carlton V Kong K Buno I et al. Immunoglobulin and T-cell receptor gene high-throughput sequencing quantifies minimal residual disease in acute lymphoblastic leukemia and predicts post-transplant relapse and survival. Biol Blood Marrow Transplant. (2014) 20:1307–13. 10.1016/j.bbmt.2014.04.018 24769317
Bartram J Goulden N Wright G Adams S Brooks T Edwards D et al. High throughput sequencing in acute lymphoblastic leukemia reveals clonal architecture of central nervous system and bone marrow compartments. Haematologica. (2018) 103:e110–4. 10.3324/haematol.2017.174987 29217777
Bahjat M Guikema JEJ. The complex interplay between DNA injury and repair in enzymatically induced mutagenesis and DNA damage in B lymphocytes. Int J Mol Sci. (2017) 18:1876. 10.3390/ijms18091876 28867784
Papaemmanuil E Rapado I Li Y Potter NE Wedge DC Tubio J et al. RAG-mediated recombination is the predominant driver of oncogenic rearrangement in ETV6-RUNX1 acute lymphoblastic leukemia. Nat Genet. (2014) 46:116–25. 10.1038/ng.2874 24413735
Mullighan CG Miller CB Radtke I Phillips LA Dalton J Ma J et al. BCR-ABL1 lymphoblastic leukaemia is characterized by the deletion of Ikaros. Nature. (2008) 453:110–4. 10.1038/nature06866 18408710
Malouf C Ottersbach K. Molecular processes involved in B cell acute lymphoblastic leukaemia. Cell Mol Life Sci. (2018) 75:417–46. 10.1007/s00018-017-2620-z 28819864
De Moerloose B Suciu S Bertrand Y Mazingue F Robert A Uyttebroeck A et al. Improved outcome with pulses of vincristine and corticosteroids in continuation therapy of children with average risk acute lymphoblastic leukemia (ALL) and lymphoblastic non-Hodgkin lymphoma (NHL): report of the EORTC randomized phase 3 trial 58951. Blood. (2010) 116:36–44. 10.1182/blood-2009-10-247965 20407035
Domenech C Suciu S De Moerloose B Mazingue F Plat G Ferster A et al. Dexamethasone (6 mg/m2/day) and prednisolone (60 mg/m2/day) were equally effective as induction therapy for childhood acute lymphoblastic leukemia in the EORTC CLG 58951 randomized trial. Haematologica. (2014) 99:1220–7. 10.3324/haematol.2014.103507 24727815
Wu D Emerson RO Sherwood A Loh ML Angiolillo A Howie B et al. Detection of minimal residual disease in B lymphoblastic leukemia by high-throughput sequencing of IGH. Clin Cancer Res. (2014) 20:4540–8. 10.1158/1078-0432.CCR-13-3231 24970842
Smith M Arthur D Camitta B Carroll AJ Crist W Gaynon P et al. Uniform approach to risk classification and treatment assignment for children with acute lymphoblastic leukemia. J Clin Oncol. (1996) 14:18–24. 10.1200/JCO.1996.14.1.18 8558195
Dastugue N Suciu S Plat G Speleman F Cavé H Girard S et al. Hyperdiploidy with 58-66 chromosomes in childhood B-acute lymphoblastic leukemia is highly curable: 58951 CLG-EORTC results. Blood. (2013) 121:2415–23. 10.1182/blood-2012-06-437681 23321258
Alves-Pereira CF de Freitas R Lopes T Gardner R Marta F Vieira P et al. Independent recruitment of Igh alleles in V(D)J recombination. Nat Commun. (2014) 5:5623. 10.1038/ncomms6623 25517887
Theunissen PMJ van Zessen D Stubbs AP Faham M Zwaan CM van Dongen JJM et al. Antigen receptor sequencing of paired bone marrow samples shows homogeneous distribution of acute lymphoblastic leukemia subclones. Haematologica. (2017) 102:1869–77. 10.3324/haematol.2017.171454 28860343
Bhojwani D Pei D Sandlund JT Jeha S Ribeiro RC Rubnitz JE et al. ETV6-RUNX1-positive childhood acute lymphoblastic leukemia: improved outcome with contemporary therapy. Leukemia. (2012) 26:265–70. 10.1038/leu.2011.227 21869842
Hübner S Cazzaniga G Flohr T van der Velden VHJ Konrad M Pötschger U et al. High incidence and unique features of antigen receptor gene rearrangements in TEL-AML1-positive leukemias. Leukemia. (2004) 18:84–91. 10.1038/sj.leu.2403182 14574333
Greaves MF Wiemels J. Origins of chromosome translocations in childhood leukaemia. Nat Rev Cancer. (2003) 3:639–49. 10.1038/nrc1164 12951583
Heinäniemi M Vuorenmaa T Teppo S Kaikkonen MU Bouvy-Liivrand M Mehtonen J et al. Transcription-coupled genetic instability marks acute lymphoblastic leukemia structural variation hotspots. eLife. (2016) 5:e13087. 10.7554/eLife.13087 27431763
Swaminathan S Klemm L Park E Papaemmanuil E Ford A Kweon S-M et al. Mechanisms of clonal evolution in childhood acute lymphoblastic leukemia. Nat Immunol. (2015) 16:766–74. 10.1038/ni.3160 25985233
Schatz DG Swanson PC. V(D)J recombination: mechanisms of initiation. Ann Rev Genet. (2011) 45:167–202. 10.1146/annurev-genet-110410-132552 21854230
Biondi A Schrappe M De Lorenzo P Castor A Lucchini G Gandemer V et al. Imatinib after induction for treatment of children and adolescents with Philadelphia-chromosome-positive acute lymphoblastic leukaemia (EsPhALL): a randomised, open-label, intergroup study. Lancet Oncol. (2012) 13:936–45. 10.1016/S1470-2045(12)70377-7
Bardini M Woll PS Corral L Luc S Wittmann L Ma Z et al. Clonal variegation and dynamic competition of leukemia-initiating cells in infant acute lymphoblastic leukemia with MLL rearrangement. Leukemia. (2015) 29:38–50. 10.1038/leu.2014.154 24798483
McHale CM Smith MT. Prenatal origin of chromosomal translocations in acute childhood leukemia: implications and future directions. Am J Hematol. (2004) 75:254–7. 10.1002/ajh.20030 15054823
Gawad C Koh W Quake SR. Dissecting the clonal origins of childhood acute lymphoblastic leukemia by single-cell genomics. PNAS. (2014) 111:17947–52. 10.1073/pnas.1420822111 25425670
Mullighan CG Phillips LA Su X Ma J Miller CB Shurtleff SA et al. Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. Science. (2008) 322:1377–80. 10.1126/science.1164266 19039135
Ribera J Zamora L Morgades M Mallo M Solanes N Batlle M et al. Copy number profiling of adult relapsed B-cell precursor acute lymphoblastic leukemia reveals potential leukemia progression mechanisms. Genes Chromosomes Cancer. (2017) 56:810–20. 10.1002/gcc.22486 28758283
Ding L-W Tan K-T Sun Q-Y Lao Z-T Yang H Jiang N et al. Clonality and clonal evolution analysis of paediatric all based on B-cell receptor/T-cell receptor rearrangement. Br J Haematol. (2019) 184:829–33. 10.1111/bjh.15179 29532914
Salson M Giraud M Caillault A Grardel N Duployez N Ferret Y et al. High-throughput sequencing in acute lymphoblastic leukemia: follow-up of minimal residual disease and emergence of new clones. Leuk Res. (2017) 53:1–7. 10.1016/j.leukres.2016.11.009 27930944
Shin S Hwang IS Kim J Lee K-A Lee S-T Choi JR. Detection of immunoglobulin heavy chain gene clonality by next-generation sequencing for minimal residual disease monitoring in B-lymphoblastic leukemia. Ann Lab Med. (2017) 37:331–5. 10.3343/alm.2017.37.4.331 28445014
Tasian SK Loh ML Hunger SP. Childhood acute lymphoblastic leukemia: integrating genomics into therapy. Cancer. (2015) 121:3577–90. 10.1002/cncr.29573 26194091
Lalonde E Wertheim G Li MM. Clinical impact of genomic information in pediatric leukemia. Front Pediatr. (2017) 5:263. 10.3389/fped.2017.00263 29312903
Szczepañski T Langerak AW Wolvers-Tettero IL Ossenkoppele GJ Verhoef G Stul M et al. Immunoglobulin and T cell receptor gene rearrangement patterns in acute lymphoblastic leukemia are less mature in adults than in children: implications for selection of PCR targets for detection of minimal residual disease. Leukemia. (1998) 12:1081–8. 10.1038/sj.leu.2401071 9665194
Meleshko AN Belevtsev MV Savitskaja TV Potapnev MP. The incidence of T-cell receptor gene rearrangements in childhood B-lineage acute lymphoblastic leukemia is related to immunophenotype and fusion oncogene expression. Leuk Res. (2006) 30:795–800. 10.1016/j.leukres.2005.11.007 16386788
Ding L-W Sun Q-Y Tan K-T Chien W Mayakonda A Yeoh AEJ et al. Mutational landscape of pediatric acute lymphoblastic leukemia. Cancer Res. (2017) 77:390–400. 10.1158/0008-5472.CAN-16-1303 27872090
Müschen M. Rationale for targeting the pre-B-cell receptor signaling pathway in acute lymphoblastic leukemia. Blood. (2015) 125:3688–93. 10.1182/blood-2015-01-567842 25878119
Brumpt C Delabesse E Beldjord K Davi F Cayuela JM Millien C et al. The incidence of clonal T-cell receptor rearrangements in B-cell precursor acute lymphoblastic leukemia varies with age and genotype. Blood. (2000) 96:2254–61. 10979974
van der Velden VHJ Szczepanski T Wijkhuijs JM Hart PG Hoogeveen PG Hop WCJ et al. Age-related patterns of immunoglobulin and T-cell receptor gene rearrangements in precursor-B-ALL: implications for detection of minimal residual disease. Leukemia. (2003) 17:1834–44. 10.1038/sj.leu.2403038 12970784
Albertí-Servera L Demeyer S Govaerts I Swings T De Bie J Gielen O et al. Single-cell DNA amplicon sequencing reveals clonal heterogeneity and evolution in T-cell acute lymphoblastic leukemia. Blood. (2021) 137:801–11. 10.1182/blood.2020006996 32812017
