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.
Advances in pharmacomicrobiomics have shed light on the pathophysiology of drug‐induced enteropathy associated with the therapeutic use of certain non‐steroidal anti‐inflammatory drugs, anticancer chemotherapies and immunosuppressants. The toxicity pathway results from the post‐glucuronidation release and digestive accumulation of an aglycone generated in the context of intestinal dysbiosis characterized by the expansion of β‐glucuronidase‐expressing bacteria. The active aglycone could trigger direct or indirect inflammatory signaling on the gut epithelium. Therefore, taming bacterial β‐glucuronidase (GUS) activity is a druggable target for preventing drug‐induced enteropathy. In face of the limitations of antibiotic strategies that can worsen intestinal dysbiosis and impair immune functions, we hereby propose the use of a recombinant probiotic capable of mimicking repressive conditions of GUS through an inducible plasmid vector.
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