Insights into IGH clonal evolution in BCP-ALL: frequency, mechanisms, associations, and diagnostic implications

Franziska Darzentas; Monika Szczepanowski; Michaela Kotrová; Alina Hartmann; Thomas Beder; Nicola Gökbuget; Stefan Schwartz; Lorenz Bastian; Claudia Dorothea Baldus; Karol Pál; Nikos Darzentas; Monika Brüggemann

doi:10.3389/fimmu.2023.1125017

Insights into IGH clonal evolution in BCP-ALL: frequency, mechanisms, associations, and diagnostic implications

Front Immunol. 2023 Apr 18:14:1125017. doi: 10.3389/fimmu.2023.1125017. eCollection 2023.

Authors

Franziska Darzentas¹, Monika Szczepanowski¹, Michaela Kotrová¹, Alina Hartmann^{1

2

3}, Thomas Beder^{1

2}, Nicola Gökbuget⁴, Stefan Schwartz^{5

6}, Lorenz Bastian^{1

2

3}, Claudia Dorothea Baldus^{1

2

3}, Karol Pál⁷, Nikos Darzentas¹, Monika Brüggemann^{1

2

3}

Affiliations

¹ Medical Department II, Hematology and Oncology, University Hospital Schleswig-Holstein, Kiel, Germany.
² University Cancer Center Schleswig-Holstein (UCCSH), University Hospital Schleswig-Holstein, Kiel, Germany.
³ Clinical Research Unit "CATCH-ALL" (KFO 5010/1), funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation), Bonn, Germany.
⁴ Department of Medicine II, Hematology/Oncology, Goethe University Hospital, Frankfurt/M, Germany.
⁵ Department of Hematology, Oncology and Tumor Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
⁶ German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁷ Central European Institute of Technology, Masaryk University, Brno, Czechia.

Abstract

Introduction: 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_H 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.

Methods: Utilizing high-throughput sequencing assays and bespoke bioinformatics we identified BCP-ALL-derived clonally-related IGH sequences by their shared 'DNJ-stem'.

Results: We introduce the concept of 'marker DNJ-stem' 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_H/V_H-DJ_H recombination and V_H 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_H/V_H-DJ_H recombination were associated with the presence of KMT2A gene rearrangements, while V_H 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.

Discussion: 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_H and DJ_H 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.

Keywords: DNJ-stem; IGH rearrangements; VH replacement; acute lymphoblastic leukemia; clonal evolution; high-throughput sequencing; minimal residual disease.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Bone Marrow / pathology
Burkitt Lymphoma* / genetics
Genes, Immunoglobulin
Humans
Polymerase Chain Reaction
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma* / diagnosis
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma* / genetics

Grants and funding

This work was supported by the Deutsche José Carreras Leukämie-Stiftung (grants DJCLS R 15/11 and DJCLS 06R/2019) to MS and MB as well as by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - project number 444949889 (KFO 5010/1 Clinical Research Unit ‘CATCH ALL’) to LB, AH, MB, and CDB.