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. 2021 Dec 21;11:771669. doi: 10.3389/fonc.2021.771669

Figure 1.

Figure 1

Compounding effect of molecular determinants of BCR signaling and recurrent mutations in genetically predisposed and sporadic origin CLL. (A) A schematic hourglass portrays the course of B cell development, selection, peripheral maintenance, activation and differentiation regulated through tight controls and varying strength of BCR signaling. As shown, each stage represents a predominant type of BCR (or pre-BCR) signaling, which controls the outcome as follows, 1) cell-autonomous signaling at bone marrow dwelled development and selection, 2) tonic signal at the mature peripheral compartments, and 3) antigen responsiveness or ligand-dependent activation signal for memory and plasma cell differentiation during the germinal center reaction. (B) Mutations that supersede the balance between BCR signal strength and developmental stages are a threat for genetic predisposition of leukemia. For example, a selection failure or gain-of-autonomous signaling mutation result in persisting autonomously active B clones in the peripheral compartment that promote proliferative boosts and prime de novo germinal center (GC) formations. In contrast, sporadic mutations have diverse origins. For example, a leukemogenic event occurring at haemopoietic stem cells (HSC) undergoing stochastic transformation might lead to anti-apoptosis and proliferation boost. (C) A stochastic model of neoplastic transformation through acquisition of biomarkers on susceptible genetic background exemplified by the acquired IGLV3-21R110 mutated CLL pathogenesis. As shown, individuals carrying the allele IGLV3-21*01 are predisposed to gain-of-autonomous BCR signaling through homotypic BCR : BCR interaction stabilized by IGLV3-21R110. Although mostly eliminated and undetected in the peripheral blood of a healthy IGLV3-21*01 carrier, a single point G→C mutation, possibly induced by activation-induced cytidine deaminase (AICDA) activity, converts a Glycine (G) to Arginine at 110th residue (R110) and initiates the neoplastic transformation. The gain-of-autonomous BCR signaling and enduring survival advocate the persistent single nucleotide variations (SNV’s) stochastically in TP53, ATM, splicing factor SF3B1 and in epigenetic modifiers to culminate the leukemogenesis and develop severe CLL.