Regulation of MicroRNA in Chronic Lymphocytic Leukemia (CLL): Mechanisms and Implications

Chronic lymphocytic leukemia (CLL) is a type of cancer characterized by the accumulation of abnormal B lymphocytes in the blood, bone marrow, and lymphoid tissues. Despite advances in understanding its pathogenesis, CLL remains incurable for many patients. Recent research has highlighted the pivotal role of microRNAs (miRNAs) in the regulation of gene expression, influencing the progression and treatment response of CLL. This article explores the mechanisms by which miRNAs regulate CLL and the potential clinical implications of these findings. MicroRNAs are small, non-coding RNA molecules, typically ۲۰-۲۲ nucleotides in length, that regulate gene expression post-transcriptionally. They bind to the ۳' untranslated regions (UTRs) of target mRNAs, leading to mRNA degradation or inhibition of translation. By modulating the expression of genes involved in cell cycle control, apoptosis, and differentiation, miRNAs play crucial roles in maintaining cellular homeostasis and can contribute to the development of diseases, including cancer, when dysregulated. In CLL, several miRNAs are consistently dysregulated. For instance, miR-۱۵a and miR-۱۶-۱ are often downregulated due to deletions or mutations in chromosome ۱۳q۱۴. These miRNAs are known to target BCL۲, an anti-apoptotic protein, and their reduced expression leads to increased BCL۲ levels, promoting cell survival and contributing to CLL pathogenesis. BCL۲ is a key regulator of apoptosis, and its overexpression inhibits programmed cell death, allowing CLL cells to evade normal cellular controls and accumulate. Epigenetic changes, such as DNA methylation and histone modifications, can also alter miRNA expression in CLL. Hypermethylation of miRNA promoters can silence their expression. For example, miR-۳۴a, a tumor suppressor miRNA, is frequently silenced in CLL through hypermethylation. The silencing of miR-۳۴a disrupts its ability to target and suppress oncogenic pathways, such as those involving the p۵۳ tumor suppressor gene. Restoring miR-۳۴a expression can induce apoptosis and inhibit tumor growth, suggesting its potential as a therapeutic target. miRNAs can act as oncogenes or tumor suppressors. OncomiRs, such as miR-۲۱ and miR-۱۵۵, are often upregulated in CLL and promote tumorigenesis by targeting tumor suppressor genes. miR-۲۱, for example, targets and downregulates the tumor suppressor gene PTEN, leading to increased activation of the PI۳K/AKT signaling pathway, which promotes cell survival and proliferation. Conversely, tumor suppressor miRNAs, like miR-۲۹b, are downregulated and lead to the activation of oncogenic pathways. miR-۲۹b targets genes involved in DNA methylation and chromatin remodeling, and its downregulation results in the aberrant expression of oncogenes and survival genes, contributing to CLL progression. miRNAs hold promise as biomarkers for CLL diagnosis and prognosis. Specific miRNA expression profiles can distinguish CLL from other types of leukemia and predict disease progression and patient survival. For example, high levels of miR-۱۸۱b are associated with aggressive disease and poor prognosis, while low levels of miR-۲۲۳ correlate with better clinical outcomes. These miRNA signatures can provide valuable information for personalized treatment strategies.

کلیدواژه ها:

Cll ، Micro RNA ، Mechanisms