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Study of IgH locus recombination in human normal and in pathological condition, the Chronic lymphocytic leukemia

Abstract : In normal B cells, Activation Induced-cytidine deaminase (AID) is the key enzyme for class switch recombination (CSR) and somatic hypermutation of (SHM) on the heavy chain (H) and the light chain (for SHM) of Immunoglobulin (Ig). AID is also implicated in another IgH rearrangement, the locus suicide recombination (LSR). LSR occurs in activated B cells and recombines the IgH locus between the switch µ (Sµ) region and the 3’regulatory region (3’RR) of IgH locus. LSR results in the complete deletion of the cluster of IgH constant genes. When LSR hits the active IgH locus, it induces the loss of BCR expression and the death of the concerned B cells. CSR and d LSR proceed by introduction of double strand breaks (DSB) followed by DNA repair and junction production. Chronic lymphocytic leukemia (CLL) is an indolent non-Hodgkin B cell lymphoma. CLL is characterized by the clonal expansion of tumor cells (CD5+, CD23+ CD19+). Tumor cells weakly express a B cell receptor (BCR) on the surface, it is composed in the vast majority of cases of Immunoglobulins (Ig) IgM and IgD. CLL tumor cells are rarely switched, raising the question of abnormalities in the Ig gene recombination machinery in this B cell lymphoma. In our study, and based on the count of LSR junction we identified two groups of CLL patients. A group with High LSR junction count (LSRHigh) and a group with low LSR junction count (LSRLow) based on the mean count of LSR junctions obtained in healthy peripheral mononuclear blood cells (PBMC). Deep analysis of these groups of CLL patients showed that in LSRHigh CLLs cells, the accessibility of IgH locus could be increased in a MYC dependent manner resulting in shorter survival and implying an additional MYC driven AID independent mechanism of IgH recombination. Also, LSRHigh and Low CLLs appear to be characterized by different features certainly due to different CLL tumoral transformation mechanisms. We showed also similarity of LSR junctions between CLL LSRLow samples and healthy tonsils. We propose tumoral cells, in LSRLow CLL, emerge from B cell population which is normally restricted to the compartment of B cell activation achievement.
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Submitted on : Tuesday, November 15, 2022 - 11:35:37 AM
Last modification on : Friday, November 18, 2022 - 11:02:14 AM

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  • HAL Id : tel-03853099, version 1

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Israa Al Jamal. Study of IgH locus recombination in human normal and in pathological condition, the Chronic lymphocytic leukemia. Human health and pathology. Université de Limoges; Université Libanaise, 2022. English. ⟨NNT : 2022LIMO0067⟩. ⟨tel-03853099⟩

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