HSA-MIRNA-17 – A POTENTIAL ONCOMIR IN CML

Background: Chronic Myeloid Leukemia( CML) is the first disease to be linked to a specific gene alteration i.e. the BCR-ABL1 fusion gene.The BCR-ABL1 protein posseses a constitutively active tyrosine kinase activity,and Imatinib a tyrosine kinase inhibitor (TKI), is the first line treatment for CML. However Imatinib has been found unable to completely eliminate leukemic stem cells,which escape Imatinib induced apoptosis. Increased expression of MAPK pathway proteins in response to Imatinib therapy has been suggested as a probable cause of leukemic stem cells persistence. Oncomir-1 is a polycistronic micro RNA complex, which encodes six micro RNAs- miR-17, miR-18a, miR-19a, miR-20a, miR-19b-1 and miR-92-1.  Increased oncomir-1 expression which regulates MAPK pathway at various levels, and directly regulates pre-apoptotic proteins containing BH domain, has been suggested as a reason for disease persistence and relapse of CML. This study evaluated the pathogenetic role of miR-17 component of miR-17-92 polycistron in CML. Objective – To measure the expression of microRNA 17 in peripheral blood leukocytes of newly diagnosed patients of Chronic Myeloid Leukemia and study the effect of standard care with Imatinib Mesylate on the expression level of  above miR. Study design – Hospital based Case-Control study. Setting – Department Of Biochemistry, Maulana Azad Medical College, New Delhi, Department Of Pathology, MAMC, New Delhi, Department of Medicine, LNJP Hospital, New Delhi. Subjects – 35 newly diagnosed CML cases in chronic phase of disease and 35 age and sex matched healthy controls. Methods – The expression of microRNA 17 in peripheral blood mononuclear cells (PBMCs) of  35 CML cases in chronic phase, in comparison to 35 age and sex matched healthy control subjects was carried out. RNA was extracted from PBMCs of  both CML patients and controls using Trizol reagent. Expression studies were performed by SYBR green based qRT-PCR and results were expressed as mean fold change. Expression of miR-17 was measured on two occasions i.e. in newly diagnosed untreated CML patients, and after 6 months of therapy with Imatinib. Result – The expression of miR-17 in PBMCs of untreated CML patients was up regulated with respect to healthy control subjects at statistically significant levels  (p<0.001). A re-evaluation of miR19b levels after six months treatment with Imatinib, revealed statistically significant down regulation of expression ,compared to the pre-therapy status(p <0.001). Conclusion – The miR-17 functions as an oncomir in the pathogenesis of CML.The consistent down regulation of miR-17 expression in CML patients after Imatinib therapy, suggests that miR-17 could be a downstream component of BCR-ABL tyrosine kinase signaling pathway. The role of miR-17 in persistence of leukemic stem cells after theray with TKIs, needs to be further dissected.