Epigenetics, the modification of chromosomes without altering DNA sequences, serves as a crucial regulatory mechanism for gene expression. Among the various epigenetic marks, N6-methyladenosine (m6A) modifications on RNA have gained significant attention in recent years for their role in various biological processes, including cancer development and progression. This article reviews the latest advances in understanding the role of m6A modifications in leukemia, a heterogeneous group of hematological malignancies.
Role of m6A Modification in Leukemia
m6A Writers and Erasers
m6A modifications are mediated by "writers" (e.g., METTL3, METTL14, and WTAP) that catalyze the methylation of adenosine residues in RNA, and "erasers" (e.g., ALKBH5 and FTO) that remove these methyl groups. These enzymes play crucial roles in regulating the balance of m6A levels in leukemia cells.
Recent studies have demonstrated that dysregulation of m6A writers and erasers can significantly impact leukemia development and progression. For instance, knockdown of METTL3 in hematopoietic stem and progenitor cells (HSPCs) leads to reduced cell growth and increased myeloid differentiation, whereas METTL14 depletion impairs self-renewal capacity of HSPCs and promotes myeloid differentiation.
Functional Implications
m6A modifications affect various aspects of RNA metabolism, including splicing, stability, translation, and subcellular localization. In leukemia, these modifications have been shown to regulate cell differentiation, proliferation, and self-renewal capacity. For example, m6A-modified mRNAs involved in hematopoiesis are differentially expressed in leukemic cells, leading to disrupted hematopoiesis and enhanced leukemogenesis.
Specific Leukemia Types
Therapeutic Implications
Given the important role of m6A modifications in leukemia, targeting these modifications represents a promising therapeutic strategy. Small-molecule inhibitors of m6A writers and demethylases have shown efficacy in preclinical models of leukemia, particularly in reducing proliferation and inducing apoptosis of leukemic cells.
Furthermore, understanding the mechanisms underlying m6A-mediated regulation of leukemic cell survival, proliferation, and differentiation can guide the development of more targeted and effective therapies.
Conclusions
m6A RNA modifications are key players in leukemia regulation, affecting various aspects of leukemic cell biology. Recent advances in understanding the mechanisms underlying m6A-mediated regulation of gene expression and leukemia development have opened new avenues for targeted interventions. As we continue to unravel the complexities of m6A modifications in leukemia, we can expect the development of more effective and personalized therapies for this devastating group of hematological malignancies.
https://www.xiahepublishing.com/1555-3884/GE-2024-00030
The study was recently published in the Gene Expression .
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Gene Expression
N6-methyladenosine (m6A) RNA Modification’s Regulatory Role in Acute and Chronic Leukemia
2-Aug-2024