Chronic lymphocytic leukemia (CLL) is an incurable indolent non-Hodgkin lymphoma characterized by tumor B-cells that weakly express a B-cell receptor (BCR). 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 (COO). Mutated IGHV gene CLLs (mCLLs) are genetically imprinted by activation induced-cytidine deaminase (AID). AID is also required for IGH rearrangements: class switch recombination (CSR) 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 CLLs into two groups on the basis of Sμ-3’RRrec counts per sample: Sμ-3’RRrecHigh cases (mostly umCLLs) and Sμ-3’RRrecLow cases (mostly mCLLs), but not based on CSR 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 CLLs harbor a non-GC experienced B-cell imprint while Sμ- 3’RRrecLow CLLs 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.
In normal activated B-cells, Activation Induced-cytidine deaminase (AID) is absolutely required for immunoglobulin (Ig) class switch recombination (CSR) and IGHV somatic hypermutation (SHM). AID is also implicated in the Locus Suicide Recombination (LSR) of the Ig heavy (IgH) locus, resulting in the deletion of the IgH constant part. Chronic lymphocytic leukemia (CLL) is an indolent non-Hodgkin B-cell lymphoma characterized by tumor CLL B-cells that weakly express a B cell receptor (BCR) on their surface. The great majority of CLL tumor B-cells are non class-switched. Searching for abnormalities of IgH locus recombination in CLL, we investigated CSR and LSR in samples from CLL patients (N=47) with high blood tumor cell infiltration (>98%) and in healthy volunteers (HV) as controls (N=9). LSR was detectable at comparable levels in both HV and CLL groups. CSR counts were decreased in CLL samples as expected. As distribution of LSR counts was bimodal, we separated CLL patients in two groups so called LSRHigh and LSRLow. LSRHigh CLLs exhibited very weak AID expression and low mutation rate of IgHV region and of the AID off-target PIM1 gene. LSR junction diversity, evaluated using the Shannon index, was increased in LSRHigh CLLs suggesting that LSR was on-going in these cells. Also, shorter telomeres were observed in LSRHigh CLLs suggesting an increased number of past mitosis. Consistently, increased levels of cMYC expression were detected in LSRHigh CLLs and treatment free survival of these cases was markedly decreased. We hypothesized that LSR in LSRHigh CLLs is AID independent and could be due to DNA lesion and inaccurate DSB repair within the IgH locus which could be accessible to recombination machinery due to increased IgH locus transcription. Altogether, our results indicate the accessibility of IgH locus and the proliferation increase LSR rate in LSRHigh CLLs could be related to cMYC resulting in shorter treatment free survival of patients and point on an AID independent mechanism of IgH recombination.
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