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

Israa Al Jamal, Milène Parquet, Kenza Guiyedi, Said Aoufouchi, Morwenna Le Guillou, David Rizzo, Justine Pollet, Marine Dupont, Mélanie Boulin, Nathalie Faumont, Hend Boutouil, Fabrice Jardin, Philippe Ruminy, Chahrazed El Hamel, Justine Lerat, Samar Al Hamaoui, Nehman Makdissy, Jean Feuillard, Nathalie Gachard, Sophie Peron

Résultats de recherche: Contribution à un journalArticleRevue par des pairs

2 Citations (Scopus)

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 (Sm) and the 3’ regulatory region (3’RR) (Sm-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 Sm-3’RRrec counts per sample: Sm-3’RRrecHigh cases (mostly unmutated CLL) and Sm-3’RRrecLow cases (mostly mutated CLL), but not based on the class switch recombination junction counts. Sm-3’RRrec appeared to be ongoing in Sm-3’RRrecHigh CLL cells and comparison of Sm-3’RRrec junction structural features pointed to different B-cell origins for both groups. In accordance with IGHV mutational status and PIM1 mutation rate, Sm-3’RRrecHigh CLL harbor a non-germinal center experienced B-cell imprint while Sm-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 Sm-3’RRrec in Sm-3’RRrecHigh cells appeared to presumably be the consequence of high c-MYC expression, as c-MYC overexpression potentiated IGH rearrangements and Sm-3’RRrec, even in the absence of AID for the latter.

langue originaleAnglais
Pages (de - à)466-478
Nombre de pages13
journalHaematologica
Volume109
Numéro de publication2
Les DOIs
étatPublié - 1 févr. 2024
Modification externeOui

Contient cette citation