RIZ1 Gene Promoter Methylation Increases with Progression of Chronic Myeloid Leukaemia to Advanced Phases

Back ground:

Chronic myeloid leukaemia CML is a clonal disorder with Philadelphia Ph chromosome as the sole genetic abnormality. The heterogeneity of CML is due to additional genetic aberrations which may include SNPs, mutations, epigenetic alterations of various tumor suppressor or cell cycle regulatory genes and even their abarent expression pattern. Epigenetic changes like histone DNA methylation, histone acetylation, microRNA expression have an important role in disease prognosis and drug resistance in CML. Tumor suppressor genes are the key targets of promoter hypermethylation in cancer. The role of DNA methylation on progression of CML and response to drug therapy has not been elucidated completely. We studied 100 CML patients in different clinical phases, 50 CP, 25 AP and 25 BC, and 100 healthy controls to elucidate the role of RIZ1 gene in chronic myeloid leukaemia CML.

Methodology:

We characterized RIZ1 gene promoter methylation and expression in 100 CML patients, 50 Chronic phase, 25 Accelerated phase and 25 Blast crisis, recruited from Lok Nayak Hospital, Maulana Azad Medical College, New Delhi, with respect 100 age and sex matched healthy controls. RIZ1 promoter methylation was studied by methylation specific PCR (MS-PCR). RIZ1 gene expression study was performed using SYBR green based qRT-PCR and the results were expressed as mean fold change.

Results:

In this study, it was found that RIZ1 gene promoter methylation significantly p 0.009 increases with CML disease progression to advanced phases. Also, RIZ1 promoter methylation was also found to be significantly associated with haematological p less than 0.01 and molecular (p less than 0.003) response of patients to Imatinib. Patients with RIZ1 promoter methylation showed a higher survival (12.66 plus minus 2.14 months) in comparison to patients without RIZ1 promoter methylation (40.75 plus minus 2.11 months) with a statistically significant p value of 0.0001.

The RIZ1 gene expression was found to decrease progressively during the progression of CML disease with 0.16, 0.6 and 1.5 fold decreased expression in CP, AP and BC phases respectively. Moreover, patients with RIZ1 promoter methylation had a lower RIZ1 gene expression pattern compared to patients without RIZ1 promoter methylation p 0.0008.

Conclusion:

Thus, it may be concluded that RIZ1 gene promoter methylation increases and its expression decreases progressively during CML disease advancement. Hence, this may be cause among other for poor drug response of some CML patients to Imatinib therapy.