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Fig. 2 | Experimental Hematology & Oncology

Fig. 2

From: Genetic pathogenesis of immunoglobulin light chain amyloidosis: basic characteristics and clinical applications

Fig. 2

Amyloid formation of AL amyloidosis in a genetic base. Primary cytogenetic aberrations, including IgH translocation and hyperdiploidy, upregulate the cyclin D (CCND) gene family, which then forms complexes with cyclin-dependent kinase 4 (CDK4) and CDK6. As a consequence, the retinoblastoma protein 1 (Rb1) is phosphorylated, releasing transcription factor E2F. This transcription factor initiates the transcription of genes necessary for G1-to-S phase transition and results in plasma cell proliferation. Secondary cytogenetic events, including 1q21 gain and loss of 13q, can exacerbate the uncontrolled cell proliferation by promoting CCND-CDK activity and impairing Rb1 function, respectively. Deletion of 17p and other driver mutations also promote plasmacytosis through other pathways. This large number of plasma cells produce excess light chains that then deposit in different tissues. Meanwhile, IgH translocation may disrupt the IgH expression or structure and lead to low intact immunoglobulin but high free light chain level. Moreover, the specific usages of immunoglobulin light chain (IgL) germline genes facilitate amyloid deposition in specific organs, and somatic mutations in IgL can produce unstable light chains that are more likely to form fibrils. CKS1B: cyclin kinase subunit 1B; MMSET: multiple myeloma SET domain; FGFR3: fibroblast growth-factor receptor 3; MAF, MAF-B & E2F: transcription factor; P: phosphorylation

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