Gadd 45 g Gene Inactivation by Promoter Hypermethylation and Chronic Myeloid Leukemia Progression : Pilot Study

Background: Chronic Myelogenous Leukemia (CML) is hematological cancer. Based on disease progression CML has three phases: chronic phase, accelerated phase and blast crisis phase. Most of the patients remain undiagnosed until and unless specific test for Philadelphia chromosome was performed. So if CML Patients remains untreated; progress from chronic phase to accelerated and then blast crisis which is medical emergency. So identification of progression of CML from CP to AP and AP to BC in early phase before terminal blast crisis phase is very important. The mechanism that leads to disease progression is not exactly known. There are many possible Genetic and Epigenetic Mechanism that leads to CML progression. Promoter hypermethylation is one of the possible epigenetic mechanisms that leads to inactivation of tumor suppressor gene in hematological malignancies. GADD45G is one of the tumor suppressor gene among panel of tumor suppressor genes involved in cancers especially hematological malignancy. That’s why Aim of our study was: Can we use Promoter hypermethylation status of GADD45G gene as follow up prognostic biomarker for CML patients who are high risk for progression? If yes; specific targeted therapy for such epigenetic change must be developed to prevent further progression of CML. Materials and methods: The study was carried out in 30 cases of CML which includes 10 patients of each phase of CML (Chronic Phase, Accelerated Phase, and Blast Crisis) patients and 30 healthy controls. Methylation status of GADD45G gene was evaluated by Methylation specific-PCR Results: Frequency of promoter hypermethylation of GADD45G gene in whole blood of CML patients 40%. We observed statistically significant difference in methylation status of genes in whole blood DNA with cases (30 CML patients) and controls (30 healthy controls) (p-value <0.0001 by Fisher exact test), But We found that there is no significant association between methylation status of GADD45G with clinical stages of CML patients (p-value=0.03 by Fisher exact test) Conclusions: Promoter hypermethylation of GADD45G is an important mechanism for GADD45G gene inactivation in CML patients. GADD45G gene inactivation leads to progression of CP to AP and AP to BC in CML patients. We found that there is no significant association between methylation status of GADD45G with clinical stages of CML patients (p-value=0.03 by Fisher exact test), But we did this study as pilot study so need to be study with large sample size. -------------------------------------------------------------------------------------------------------------------------------------Date of Submission: 11-03-2019 Date of acceptance: 27-03-2019 -------------------------------------------------------------------------------------------------------------------------------------