Inactivation of RIZ1 Gene by Promoter Hypermethylation is Associated with Disease Progression and Resistance to Imatinib in Indian Chronic Myelogenous Leukemia Patients, First Study from India
Imtiyaz Ahmad1#, Rashid Mir1#,Mariyam Zuberi1, Jamsheed Javid1, Prasant Yadav1, Shazia Farooq1, M. Masroor1, Sameer Guru1, Sheikh Shahnawaz1, P C Ray1, Ishfaq Ahmed Sheikh2, Tanvir Khatlani3, Ajaz Ah Bhat4, Naresh Gupta5, Sunita Jetly6, Niyaz Ahmad7 and Alpana Saxena8*
- *Corresponding Author:
- Dr Alpana saxena
Director Professor and Head
Department of Biochemistry
Maulana Azad Medical College and Associated Hospitals
New Delhi 110002
E-mail: [email protected]
Received date: November 04, 2012; Accepted date: December 26, 2012; Published date: December 28, 2012
Citation: Imtiyaz Ahmad AB, Mir R, Zuberi M, Javid J, Yadav P, et al. (2013) Inactivation of RIZ1 Gene by Promoter Hypermethylation is Associated with Disease Progression and Resistance to Imatinib in Indian Chronic Myelogenous Leukemia Patients, First Study from India. J Cancer Sci Ther 5:045-051. doi: 10.4172/1948-5956.1000183
Copyright: © 2013 Imtiyaz Ahmad AB, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Background: The epigenetic impact of DNA methylation in chronic myelogenous leukemia (CML) is not
completely understood. RIZ1 expression and activity are reduced in many cancers. In CML, blastic transformation is associated with loss of heterozygosity in the region where RIZ1 is located. RIZ1 is a PR domain methyltransferase that methylates histone H3 lysine 9, a modification important for transcriptional repression. In CML blast crisis cell lines RIZ1 represses insulin-like growth factor-1 expression and autocrine signaling. Together these observations suggest that RIZ1 may have a role in the chronic phase to blast crisis transition in CML. Methods: To examine whether promoter methylation is involved in the disease development and progression of CML, we investigated promoter methylation status of RIZ1 gene in 100 chronic myeloid leukemia’s (CML) patients and 50 controls by MSP method.
Results: The RIZ1 methylation was studied in 100 CML patients, 9 were cases were methylation positive
cases, six of nine were in blastic phase, 2 in chronic phase and one patient in accelerated phase. It was seen that RIZ1 methylation was increased significantly from early to advanced phase. The higher frequency of RIZ1 methylation was reported in haematologically resistant cases (42% vs 2%) and molecularly resistant cases (16.77% vs 1.92%) than the responders. The higher frequency of RIZ1 methylation was found in CML patients who were treated with interferon initially followed by imatinib treatment. Also RIZ1 hypermethylation was associated with faster disease progression p<0.003 than the non methylated cases. No correlation was found between RIZ1 gene methylation with age, thrombocytopenia, types of bcr/abl transcripts of CML patients.
Conclusion: We conclude that epigenetic silencing of RIZ1 gene is associated with CML progression and
imatinib resistance. Early detection of RIZ1 methylation could be a predictive marker for imatinib resistance and disease progression in CML.