B-cell receptor signaling in chronic lymphocytic leukemia Assistant Prof. Dr. Nibras Saleam Al-Ammar PhD in Clinical Immunology Pathology Department

Chronic lymphocytic leukemia (CLL) Is a malignant disorder of mature B cells that is characterized by monoclonal expansion in blood, bone marrow, and lymphoid organs of cells arrested in the G0/G1 stage of the cell cycle.

One approach to understanding CLL is to investigate the nature of intracellular signals responsible for the development and prolonged survival of the malignant cells

structural restrictions of the BCR BCR-dependent survival BCR signaling plays an important pathogenic role in chronic lymphocytic leukemia (CLL) and based on: structural restrictions of the BCR BCR-dependent survival growth of the malignant B cells

BCR activation can be induced by: antigen or can be ligand-independent (“tonic” BCR signaling)

BCR activation triggers a cascade of signaling events that normally cause: B cell selection proliferation differentiation antibody production

BCR activation in the CLL: mechanism and relationship with prognostic markers The BCR is composed of (smIg), paired with the signal transduction moiety, Ig-α/Ig-β heterodimers (CD79A, CD79B). Engagement of the BCR by antigen induces membrane movement and aggregation of BCR components that lead to phosphorylation of ITAMs in the cytoplasmic tails of CD79A and CD79B.

IGHV mutational status During early B cell differentiation, the gremline variable (V), diversity (D), and joining (J) gene segments of Ig gene complexes rearrange and each B-lymphocyte thereby obtains a particular combination of V-(D-)J segments. Combination Rearrangement V- D-J V D J VDJ The germline gene segments

BCRs in CLL patients are characterized by a biased usage of IGHV and IGLVκ/λ genes, which differ from those of normal B cells.

Based on the degree of somatic hyper mutation of the IGHVs: “unmutated” (U-CLL), have ≥ 98% sequence homology with the germline sequence. or “mutated” (M-CLL) cases, have < 98% sequence homology.

BCR-related risk factors in CLL IGHV mutational status ZAP-70 CCL3, CCL4 , MIP-1

Methods of detection:

IGHV mutational status 1. DNA extraction, 2. PCR amplification & 3. Sequencing

ZAP-70 1. Western blotting, 2. quantitative RT-PCR, and 3. Immunohistochemistry

CCL3, CCL4 , MIP-1 1. ELISA

Targeting BCR signaling in CLL For therapeutic purposes: a. antigen deprivation b. interference with antigen binding c. disruption of BCR downstream signaling

Thank You