IGH 3’RR recombination uncovers a non-germinal center imprint and c-MYC-dependent IGH rearrangement in unmutated chronic lymphocytic leukemia - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Haematologica Année : 2023

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

Israa Al Jamal
  • Fonction : Auteur
Milene Parquet
  • Fonction : Auteur
Kenza Guiyedi
  • Fonction : Auteur
Morwenna Le Guillou
  • Fonction : Auteur
David Rizzo
  • Fonction : Auteur
Justine Pollet
  • Fonction : Auteur
Marine Dupont
  • Fonction : Auteur
Melanie Boulin
  • Fonction : Auteur
Nathalie Faumont
  • Fonction : Auteur
Hend Boutouil
  • Fonction : Auteur
Fabrice Jardin
  • Fonction : Auteur
Philippe Ruminy
  • Fonction : Auteur
Chahrazed El Hamel
  • Fonction : Auteur
Justine Lerat
  • Fonction : Auteur
Samar Al Hamaoui
  • Fonction : Auteur
Nehman Makdissy
  • Fonction : Auteur
Jean Feuillard
  • Fonction : Auteur
Nathalie Gachard
  • Fonction : Auteur
Sophie Peron
  • Fonction : Auteur

Résumé

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.

Dates et versions

hal-04444055 , version 1 (07-02-2024)

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Israa Al Jamal, Milene Parquet, Kenza Guiyedi, Said Aoufouchi, Morwenna Le Guillou, et al.. IGH 3’RR recombination uncovers a non-germinal center imprint and c-MYC-dependent IGH rearrangement in unmutated chronic lymphocytic leukemia. Haematologica, In press, 109 (2), pp.466-478. ⟨10.3324/haematol.2023.282897⟩. ⟨hal-04444055⟩
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