Acute myeloid leukemia (AML) or acute non lymphoblastic leukemia (ANLL) is a clonal malignant disease of haematopoietic tissue that is characterized by the proliferation of abnormal (leukemic) myeloblast cells principally in marrow and impaired production of normal blood cells.
Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm with an incidence of 1–2 cases per 100,000 adults, and accounts for 15% of newly diagnosed cases of leukemia in adults. CML is characterized by a balanced genetic translocation, t(9;22)(q34;q11.2), involving a fusion of the Abelson oncogene (ABL) from chromosome 9q34 with the breakpoint cluster region (BCR) gene on chromosome 22q11.2.
GTPase regulator associated with focal adhesion kinase (GRAF) is a newly identified protein specifically binding to FAK and negatively regulates the small GTP-binding protein RhoA, which is well known for its growth-promoting effect in RAS-mediated malignant transformation .GRAF is recognized as a tumor suppressor gene that binds to focal adhesion kinase .
The GRAF gene is the human homologue of a recently isolated avian cDNA,The avian GRAF protein binds to the C-terminal domain of pp125FAK, stimulate the GTPase activity of the GTP-binding protein RhoA. Thus, GRAF acts as a negative regulator of RhoA. RhoA suppresses p21,a well-known inhibitor of the cell cycle, loss of function of GRAF prevents the physiologic down-regulation of RhoA. Thus, the elimination of the negative regulatory function of the GRAF may lead to the repression of p21. If so, the GRAF-defective cell will be driven into the S phase .
The aim of this study to access the expression level of GRAF gene in patients with acute myeloid leukemia (AML) and chronic myeloid leukemia (CML) and to clarify its prognostic significance on clinical outcome.
In this study, we investigated the expression of the GRAF transcript by real time quantitative PCR in 37 AML patients, 35 CML patients and 15 healthy age and sex matched controls, and to clarify its prognostic significance on clinical outcome.
In AML patients, GRAF expression was significantly lower in patients with AML when compared to controls (p0.05 for each).
Patients with high GRAF transcript levels were associated with a significantly higher CR rate .There was highly significant difference between AML patients who achieved continuous complete remission, refractory, died in induction therapy and those who relapsed (p 0.05 for each). However, basophilia and higher peripheral blasts were significantly associated with low values of Graf expression (p= 0.042, 0.008 respectively). There was significant difference in Graf expression between those who were chemotherapy responders and those who were resistant (p=0.004).
ROC curve analysis for prediction of resistance in CML patient showed that the best cutoff value for GRAF was 3.406, at this point the sensitivity was 80% and specificity was 67%. The area under the curve was 0.824 and (p |
