Mieloma multipel: aspek patogenesis molekuler
Keywords:multiple myeloma, pathogenesis, molecular
Multiple myeloma (MM) is a neoplastic plasma disorder that is characterized by clonal proliferation of malignant plasma cells in the bone marrow, monoclonal protein in the blood or urine and associated organ dysfunction. It is preceded by a premalignant tumor which is share genetic abnormalities, monoclonal gammopathy of undetermined significance (MGUS). Although remarkable progress has been achieved, but pathogenesis of MM is still very complex. Multiple myeloma appears to arise from the malignant transformation of germinal-center B-lymphocyte. The first oncogenic events in MM appear to occur in the germinal center due to error in isotype class switching and somatic hypermutation. MM is divided into two distinct genetic subtypes: (1) hyperdiploid myeloma is characterized by multiple trisomies of chromosome 3, 5, 7, 9, 11, 15, 19 and 21; (2) non-hyperdiploid in contrast is characterized by recurrence translocations t(4;14), t(14;16), t (14;20); t(6;14) and t(11;14). A unifying event in the pathogenesis of MM is the dysregulated expression of cyclin D gene. Genetic aberrations occur in MM and also in premalignant state (MGUS), suggesting that genetic mutations alone are necessary, but not sufficient for myeloma transformation. A “ random second hit model” was proposed. Hypothetical second hits are: additional genetic changes ( RAS mutation, p16 methylation, p53 mutation), proliferation due to cell cycle dysregulation, evasion of programmed cell death and changes in bone marrow microenvironment. A complex interaction with the BM microenvironment , characterized by activation of osteoclast and supression of osteoblast , leads to lytic bone lesions.
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