B Cell Lymphoma Malignancy is Associated with a Long non-coding RNA, MIAT, Expression.

ABSTRACT Hematopoietic malignancies are highly dysregulated processes in which many molecular aspects are involved. Long non-coding RNAs (lncRNAs) are increasingly recognized as important regulators of gene expression. They are functional RNAs longer than 200 nucleotides in length, with low coding potential. MIAT was originally identified as a long non-coding RNA expressed in neuronal cells and constitutes a component of the nuclear scaffold. Moreover it affects the kinetics of the splicing process. Recently, MIAT is genetically associated with heart disease. However the molecular basis of MIAT function as well as its role in human disease is still in the beginning. In the present thesis, Expression of MIAT was studied in leukemic cell lines as well as a large cohort of CLL patients. Quantitative analysis of MIAT, revealed extremely MIAT expression in B cell lymphoma, while other types of leukemia like AML, ALL and CML did not show considerable expression. Feasible prognosis of outcome in CLL sample groups was related to MIAT expression. Abundant expression of MIAT achieved in unfavorable outcomes group of CLL patient samples (trisomy 12, 17p13 deletion, 11q22 deletion) compared to favorable (13q deletion) cytogenetic group. Intriguingly, MIAT expression might be associate to aggressiveness and poor outcome in CLL which also empower a role for MIAT in leukemia. Since, genetic networks controlling MIAT expression was the focus of our intense interest, an association beyond the transcription factors, Oct4, and human MIAT transcript was also studied. We showed that mRNA and protein level of Oct4 is in direct modulation of MIAT expression in leukemic cell lines as well as CLL patient samples. RNAi mediated knockdown of MIAT transcript lead to robust changes in Oct4 mRNA level. We further characterized a regulatory feedback loop between Oct4 and MIAT by developing lentivirus shRNA to downregulate Oct4 level. We showed that a reciprocal correlation of MIAT and Oct4 regulates their expression. Most importantly, We demonstrated that suppression of either Oct4 or MIAT induced apoptosis and reduced viability in lymphoma derived cell line. In haematological malignancies, More studies on lncRNAs MIAT, may help to identify patient populations at risk of leukemia, may classify patients into aggressive or mild cancer groups and may also promisingly facilitate the derivation of conventional therapeutic interventions by transfering lncRNA research to clinical oncology.