ABSTRACT
Background: Acute Myeloid Leukemia (AML) is a heterogeneous disorder with variable genetic abnormalities and cytogenetic alterations which provide a significant disease prognosis and determine response to therapy. Purpose: We aim to investigate the expression of the MDR1 gene in 100 Egyptian AML patients, to identify their role on both the progression and chemotherapeutic refractoriness together with assessment of known prognostic molecular markers; FLT3-ITD and NPM1 mutations. Methodology: Quantitative assessment of MDR1 gene expression was performed by quantitative RT-PCR. Additional prognostic molecular markers were determined as internal tandem duplications of the FLT 3 gene and nucleophosmin gene mutation A. Results: MDR1 gene expression levels and FLT3/ITD mutations were significantly higher in AML patients with resistant disease with P value <0.001 and 0.002 respectively. However, NPM1 was insignificantly higher in patients with CR P-value 0.14. In MDR positive group, wild FLT3/ITD with or without NPM1 mutation was favorable in achieving CR with p value 0.02. MDR negative group, wild FLT3/ITD with or without NPM1 mutation showed insignificantly higher CR rates with p value (0.35). Kaplan-Meier curves revealed statistically significant difference between MDR1-negative and MDR1-positive patients regarding their DFS and OS between the two groups where DFS and OS were higher in MDR1-negative patients with p value 0.004 and 0.01, respectively. Conclusion: The results obtained by the current work together with the previous researches concerning the study of multidrug resistance genes in AML patients provide additional evidence of the role played by these genes as predictors of chemoresistance and poor treatment outcome.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Drug Resistance, Neoplasm/genetics , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Mutation , Nuclear Proteins/genetics , fms-Like Tyrosine Kinase 3/genetics , Adolescent , Adult , Aged , Biomarkers, Tumor , Case-Control Studies , Child , Child, Preschool , Egypt , Female , Follow-Up Studies , Humans , Leukemia, Myeloid, Acute/pathology , Male , Middle Aged , Nucleophosmin , Prognosis , Survival Rate , Young AdultABSTRACT
BACKGROUND: Transcription factors play a crucial role in myeloid differentiation and lineage determination. Tumor suppressor protein C/EBPa is a key regulator of granulocytic differentiation whose functional inactivation has become a pathophysiological signature of myeloid leukemia. Given the role that CCAAT/enhancer binding protein α (C/EBP α) plays in myelopoiesis, we anticipated that their expression might be disrupted in myeloid neoplasms. PURPOSE: To estimate the expression of C/EBPα mRNA in patients with acute myeloid leukemia and correlate its expression with the pathogenesis of the disease. PATIENTS AND METHODS: Forty AML patients and 20 age and sex matched healthy controls were included in the study. Blood samples of patients and controls were analyzed for CEBPα mRNA expression by quantitative RT-real time PCR using TaqMan technology & ΔΔCt method for calculation of gene expression. RESULTS: Twenty-nine (72.5%) patients out of the 40 showed low expression levels of CEBPα mRNA below the cutoff value with median of 0.19 (range:0-0.87). While eleven (27.5%) patients out of the 40 showed higher expression levels of CEBPα above the cutoff value with median of 1.52 (range:1.07-2). Seven patients out of the 11 showed higher expression levels of CEBPα mRNA belong to the M3 subtype of AML harboring the t(15;17) PML-RARa translocation. CONCLUSION: We conclude that the majority of the AML patients analyzed, express low levels of C/EBPa mRNA. However, a subset of patients represented by the M3 subtype, express higher levels of C/EBPa.
