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IGH 3'RR recombination uncovers a non-germinal center imprint and c-MYC-dependent IGH rearrangement in unmutated chronic lymphocytic leukemia.

Authors
  • Al Jamal, Israa1
  • Parquet, Milene2
  • Guiyedi, Kenza2
  • Aoufouchi, Said3
  • Le Guillou, Morwenna3
  • Rizzo, David4
  • Pollet, Justine2
  • Dupont, Marine4
  • Boulin, Melanie4
  • Faumont, Nathalie2
  • Boutouil, Hend2
  • Jardin, Fabrice5
  • Ruminy, Philippe5
  • El Hamel, Chahrazed6
  • Lerat, Justine7
  • Al Hamaoui, Samar8
  • Makdissy, Nehman8
  • Feuillard, Jean4
  • Gachard, Nathalie4
  • Peron, Sophie9
  • 1 Centre National de la Recherche Scientifique (CNRS) Unite Mixte de Recherche (UMR) 7276/INSERM U1262, Universite de Limoges, Limoges, France; Faculty of Sciences, GSBT Genomic Surveillance and Biotherapy Team, Mont Michel Campus, Lebanese University, Tripoli. , (France)
  • 2 Centre National de la Recherche Scientifique (CNRS) Unite Mixte de Recherche (UMR) 7276/INSERM U1262, Universite de Limoges, Limoges.
  • 3 CNRS UMR9019, Gustave Roussy, B-cell and Genome Plasticity Team, Villejuif, France and Universite Paris-Saclay, Orsay. , (France)
  • 4 Centre National de la Recherche Scientifique (CNRS) Unite Mixte de Recherche (UMR) 7276/INSERM U1262, Universite de Limoges, Limoges, France; Laboratoire d'Hematologie Biologique, Centre Hospitalier Universitaire de Limoges, Limoges. , (France)
  • 5 Inserm U1245 and Department of Henri-Becquerel Hematology Center and Normandie Univ UNIROUEN, Rouen.
  • 6 Collection Biologique Hopital de la Mere et de l'Enfant (CB-HME), Department of Pediatrics, Limoges University Hospital, Limoges.
  • 7 Department of Otorinolaryngology, Limoges University Hospital, Limoges.
  • 8 Faculty of Sciences, GSBT Genomic Surveillance and Biotherapy Team, Mont Michel Campus, Lebanese University, Tripoli.
  • 9 Centre National de la Recherche Scientifique (CNRS) Unite Mixte de Recherche (UMR) 7276/INSERM U1262, Universite de Limoges, Limoges. [email protected].
Type
Published Article
Journal
Haematologica
Publisher
Ferrata Storti Foundation
Publication Date
Feb 01, 2024
Volume
109
Issue
2
Pages
466–478
Identifiers
DOI: 10.3324/haematol.2023.282897
PMID: 37496419
Source
Medline
Language
English
License
Unknown

Abstract

Chronic lymphocytic leukemia (CLL) is an incurable indolent non-Hodgkin lymphoma characterized by tumor B cells that weakly express a B-cell receptor. The mutational status of the variable region (IGHV) within the immunoglobulin heavy chain (IGH) locus is an important prognosis indicator and raises the question of the CLL cell of origin. Mutated IGHV gene CLL are genetically imprinted by activation-induced cytidine deaminase (AID). AID is also required for IGH rearrangements: class switch recombination and recombination between switch Mu (Sμ) and the 3' regulatory region (3'RR) (Sμ-3'RRrec). The great majority of CLL B cells being unswitched led us to examine IGH rearrangement blockade in CLL. Our results separated CLL into two groups on the basis of Sμ-3'RRrec counts per sample: Sμ-3'RRrecHigh cases (mostly unmutated CLL) and Sμ-3'RRrecLow cases (mostly mutated CLL), but not based on the class switch recombination junction counts. Sμ-3'RRrec appeared to be ongoing in Sμ-3'RRrecHigh CLL cells and comparison of Sμ-3'RRrec junction structural features pointed to different B-cell origins for both groups. In accordance with IGHV mutational status and PIM1 mutation rate, Sμ-3'RRrecHigh CLL harbor a non-germinal center experienced B-cell imprint while Sμ-3'RRrecLow CLL are from AID-experienced B cells from a secondary lymphoid organ. In addition to the proposals already made concerning the CLL cell of origin, our study highlights that analysis of IGH recombinatory activity can identify CLL cases from different origins. Finally, on-going Sμ-3'RRrec in Sμ-3'RRrecHigh cells appeared to presumably be the consequence of high c-MYC expression, as c-MYC overexpression potentiated IGH rearrangements and Sμ-3'RRrec, even in the absence of AID for the latter.

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