Mismatch repair deficiencies transforming stem cells into cancer stem cells and therapeutic implications

For the exceptional self-renewal capacity, regulated cell proliferation and differential potential to a wide variety of cell types, the stem cells must maintain the intact genome. The cells under continuous exogenous and endogenous genotoxic stress accumulate DNA errors, drive proliferative expansion and transform into cancer stem cells with a heterogeneous population of tumor cells. These cells are a common phenomenon for the hematological malignancies and solid tumors. In response to DNA damage, the complex cellular mechanisms including cell cycle arrest, transcription induction and DNA repair are activated. The cells when exposed to cytotoxic agents, the apoptosis lead to cell death. However, the absence of repair machinery makes the cells resistant to tumor sensitizing agents and result in malignant transformation. Mismatch repair gene defects are recently identified in hematopoietic malignancies, leukemia and lymphoma cell lines. This review emphasizes the importance of MMR systems in maintaining the stem cell functioning and its therapeutic implications in the eradication of cancer stem cells and differentiated tumor cells as well. The understanding of the biological functions of mismatch repair in the stem cells and its malignant counterparts could help in developing an effective novel therapies leaving residual non-tumorigenic population of cells resulting in potential cancer cures

DNA mismatch repair, microsatellite instability and cancer

989-994Mismatch (MMR) repair system plays a significant role in restoration of stability in the genome. Mutations in mismatch repair genes hamper their activity thus bring about a defect in mismatch repair (MMR) mechanism thereby conferring instability in the microsatellite sequences of both the coding and non-coding regions of the genome. Mutated mismatch repair genes result in the expansion or contraction of microsatellite sequence and confer microsatellite unstable or replication error positive phenotype. Hypermethylation of promoter regions of some of the MMR genes also causes inactivation of these genes and thus contribute to MSI. Microsatellite instability is an indicator of MMR deficiency and is a prime cause of varied tumorogenesis

Clinicopathological and genetic study in cerebral aspergillosis and leukemic infitration in ALL

An 11-year-old neutropenic female child with acute lymphoblastic leukemia (ALL) developed a large right frontal mass a month following the induction of chemotherapy. A well encapsulated mass on surgical excision turned out to be aspergilloma with metastatic infiltration in frontal lobe. A genetic defect in form of microsatellite instability was also demonstrated in frontal mass. A possibility of fungal granuloma in a neutropenic child treated for ALL (on chemotherapy) remained strong on clinico-radiological evaluation. However, the cranial involvement in ALL also amounts to be 50 to 80% in untreated children. The child under discussion had a rare manifestation of both leukemic infiltration and fungal granuloma formation. Though the microsatellite instability was demonstrated in the mass, but further genetic studies would be required to establish the role of genetic defect in evolution of such cerebral masses/leukemic deposits. (J Pediatr Neurol 2004; 2(1): 39-43)