dc.contributor.advisor |
Khoueiry, Pierre |
dc.contributor.author |
Ashekyan, Ohanes |
dc.date.accessioned |
2022-01-11T05:02:48Z |
dc.date.available |
2022-01-11T05:02:48Z |
dc.date.issued |
1/11/2022 |
dc.date.submitted |
1/10/2022 |
dc.identifier.uri |
http://hdl.handle.net/10938/23251 |
dc.description.abstract |
Studies on mechanisms of drug resistance have extensively focused on protein-coding genes, yet cancer development and progression cannot be fully explained solely by the coding genome. Novel technologies revealed that only < 1% of the genome is protein-coding, with the non-coding genome harboring a crucial gene regulatory potential. Long non-coding RNAs (LncRNAs), which are RNA molecules greater than 200 nucleotides in length, have been presented as the main players of the non-coding genome along with their shorter microRNA (miRNA) counterparts, regulating gene expression at the transcriptional, post-transcriptional, translational, and epigenetic levels.
It has been shown that long intergenic non-coding RNA – Regulator of Reprogramming (LINC-ROR) and LINC01287 are implicated in several cancers with roles in resistance to drugs. LINC-ROR is responsive to the epigenetic drug inhibitor of bromodomain and extra-terminal proteins 151 (I-BET151) treatment at low concentrations in I-BET151-sensitive AML cell line (MV4-11) and LINC01287 was demonstrated to be differentially upregulated in I-BET151-resistant CML cell line (K562) relative to MV4-11. Here, we hypothesized that LINC-ROR and LINC01287 are the intrinsic I-BET151 sensitivity/resistance mediators of MV4-11 and K562 cell lines, respectively.
In our study, we explored LINC-ROR and LINC01287 expression profiles in cancer patients and blood cancer cell lines using publicly available cancer genome atlas (TCGA) and leukemia-lymphoma 100 (LL-100) panel datasets. We demonstrate their overexpression and uniqueness across several cancers and blood cancer cell lines of distinct cellular origins, lineages, and cancer subtypes. We also investigated in-silico lncRNA-miRNA interactions and discovered a unique role for LINC-ROR and LINC01287 in hematological malignancies through miRNA regulation. Lastly, following a fluorescently labeled siRNA-mediated gene knockdown approach coupled with cell sorting, we attempted to discover whether LINC-ROR knockdown recapitulates the effect of I-BET151 treatment on the MV4-11 cell line and if LINC01287 knockdown enhances the sensitivity of the K562 cell line to I-BET151. Interestingly, RT-qPCR on a panel of LINC01287 targets in K562 cells revealed promising trends. We further aimed to conduct RNA-sequencing but were limited with the logistics. Our findings if coupled with RNA-sequencing in the near future may provide greater support to our hypothesis and pave the way for further research on manipulating lncRNA-mediated epigenetic regulation in favor of disease treatment. |
dc.language.iso |
en_US |
dc.subject |
LncRNA |
dc.subject |
Epigenetics |
dc.subject |
MicroRNA |
dc.subject |
I-BET151 |
dc.subject |
Sensitivity |
dc.subject |
Resistance |
dc.subject |
Cancer |
dc.subject |
AML |
dc.subject |
CML |
dc.subject |
TCGA |
dc.subject |
LL-100 |
dc.title |
CHARACTERIZING THE ROLE OF LNCRNAS IN CONFERRING SENSITIVITY/RESISTANCE TO I-BET151 TREATMENT USING AN IN-VITRO MODEL OF LEUKEMIA CELL LINES |
dc.type |
Thesis |
dc.contributor.department |
Department of Biochemistry and Molecular Genetics |
dc.contributor.faculty |
Faculty of Medicine |
dc.contributor.institution |
American University of Beirut |
dc.contributor.commembers |
Darwiche, Nadine |
dc.contributor.commembers |
Nasr, Rihab |
dc.contributor.degree |
MS |
dc.contributor.AUBidnumber |
202022615 |