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Leukemia is a type of malignant neoplastic disease containing blood-forming tissue, including blood in addition to the lymphatic system. There are many sub-categories of blood cells containing platelets, white blood cells (WBCs), and red blood cells (RBCs). In general leukemia refers to cancer about leucocytes or WBCs. There are some risk factors of leukemia- smoking which increases the risk in developing Acute Myeloid Leukemia (AML), the gene-transmitted disease caused due to exposure to radiation. The general symptoms of leukemia are dehydration (vomiting, sweating), weight loss, bone pain, headache, lack of sphincter muscle command, and involuntary movements. According to worldwide report leukemia constitutes approximately 14.1% of one lakh population out of which 6.5% mortality has been reported. Leukemia occurs in adults above 55 years and children younger than 15 years. In India there are 10,000 cases of childhood leukemia has been reported. Leukemia in Indian prenatal subpopulation appears to be nearly 34. In India the total cases of leukemia have been found to be 10 lakhs every year out of which 30,000 cases are of Acute Leukemia. This review focusses on the promoter hypermethylation that plays an important role in the downregulation of Tumor suppressor genes in leukemia. Epigenetic alternations are reversible modifications in histone or DNA hypermethylation that regulate gene utilization after the underlying sequence. Another focus may be Reversal of Hypermethylation of Tumor Suppressor genes (TSGs) in Leukemia using natural compounds. Recent findings have shown the great potential of alternative interventions such as immunotherapy and natural products for leukemia.