Asian Research Thesis Index

Abstract

Acute lymphoblastic leukemia (ALL) is a hematological malignancy common in children and adult males. ALL is considered to be on the rise in Pakistan. External, physiological and genetic factors have been found to play a fundamental role in causing the cancer. In the present study, we investigated the external factors like exposure to radiations, chemicals, sunlight, smoking, electronic devices and dietary habits as potential risk factors in relation to ALL. None of these factors were found to be associated with ALL risk in Pakistani population. However, among physiological factors we found significant correlation between psychological stress and ALL incidence. Overrepresentation of B+ve blood group was noted among ALL patients. Replicative potential, telomere modulation, migration / metastasis, unlimited proliferation and metabolic reprogramming are important for tumor development. Genes including GMFG, EpCAM, PCSK9, CTC1 and OBFC1 were studied at transcriptional level to elucidate their role in ALL related to motility, proliferation, lipid metabolism and telomere modulation, respectively. The role of these genes in relation to ALL was not studied before. To study telomere modulation important for leukemia cell survival, telomere length measurement was performed. No significant changes in telomere length were observed. However, at transcriptional level, induced expression of telomere modulating genes (CTC1, OBFC1, hTERT) in ALL patients was observed which could be correlated with telomere length maintenance in leukemia cells. The induced GMFG expression, which is important for cell migration, in leukemia patients indicated that it has potential to be used as a leukemia diagnostic marker. EpCAM related to cell proliferation was not well established in ALL. Its mRNA expression was significantly upregulated in ALL patients. Similarly, PCSK9 which regulates cholesterol metabolism was also induced in ALL. mRNA expression of ALL specific genes like TAL1, BLNK and BLACE were also investigated and found to be upregulated in ALL Pakistani population. They, therefore, could potentially be used as ALL gene markers for early detection and diagnosis of leukemia.     xii  Next, in in vitro studies, naturally occurring biomolecules like costunolide and eugenol were used for identification of new therapeutic approaches with better treatment outcome. Costunolide, a potent telomerase inhibitor reduced EpCAM and its downstream target gene c-Myc and probably also contributed in inhibiting hTERT expression. Similarly, PCSK9 and LOX1 were significantly down-regulated by antioxidant eugenol. Results from this study suggested that costunolide and eugenol could plausibly be used as therapeutic biomolecules for reducing cancer cell proliferation and growth by limiting the metabolic supply.

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