الفهرس 
REVIEW OF LITERATUREOnly 14 pages are availabe for public view
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Abstract
Acute Myeloid Leukemia (AML) is an aggressive heterogeneous neoplastic disorder characterized by uncontrolled proliferation, inhibition of differentiation and accumulation of immature myeloid precursor cells in the bone marrow leading to impaired hematopoiesis and bone marrow failure. It has broad variability in the pathogenesis, clinical course, and response to therapy. The Runt-related transcription factors (RUNX) are involved in essential developmental processes. They contribute to hematopoiesis and are frequently implicated in hematologic malignancies. They act as either transcriptional activators or repressors and can be proto-oncogenes or tumor suppressors. In mammals, there are three RUNX proteins encoded by three genes: RUNX1,2 and 3 . Because of their lineage-specific expression, each RUNX gene has been studied in isolation without reference to the other two genes in the family. However, there is a growing realization that RUNX genes function in a complementary manner and must be stud¬ied concurrently. Hedgehog (HH) signaling pathway is considered as one of major developmental pathways which interact with RUNX family. The Hedgehog pathway plays an important role in stem-cell biology and malignant transformation. Therefore, we investigated the expression level and prognostic impact of RUNX family together beside Hedgehog genes in adult acute myeloid leukemia (AML) patients.
Aim of the work
The aim of the present study was to evaluate the expression levels of RUNX1,2 and 3 along with the hedgehog genes Indian hedgehog (IHH) and Sonic hedgehog (SHH) and correlated their expressions with various clinicopathological parameters.
Methods
The present study included Forty six bone marrow (BM) samples collected from newly diagnosed adults with de novo AML. The patients were presented to inpatient clinic at National Cancer Institute (NCI), Cairo University (CU). They were diagnosed between June 2015 and November 2016. Five normal samples were enrolled for normalization which Obtained from healthy donors.
Total RNA from bone marrow (BM) samples was extracted and purified, and then the complementary DNA (cDNA) was synthesized. Quantitative real time polymerase chain reaction (qRT-PCR) was used to evaluate the expression levels of RUNX1,2 and 3 along with IHH and SHH. The CT values were obtained for all genes and normalized to GAPDH. Then, the fold changes using 2−ΔΔCT method were calculated. Statistical analysis was done and the results were correlated with clinicopathological data.
Results
The present study revealed up regulation of RUNXs family on the other hand down regulation of IHH and SHH in AML patients .IHH was positively correlated with SHH and RUNX2 (r=0.949,P<0.001 and r=0.307, P=0.038).Also IHH,SHH and RUNX2 were inversely associated with CD4 expression on AML blasts(P=0.017, P=0.074 and P=0.011) respectively.RUNX3,IHH and SHH were significantly increased with advanced age (P=0.018,P=0.044 and P= 0.007).RUNX3 was positively correlated with RUNX1(r=0.302,P=0.042) and platelets (PLT) (r=0.317,P=0.032),on other hand RUNX3 was negatively associated with total leukocytic count (TLC) and peripheral blood blast (PB Blasts) (P=0.005,P=0.001)respectively.
The prognostic analysis of the present study indicated that higher expression of RUNX3 and higher Hb level were the only independent factors affecting OS in multivariate analysis (P=0.003, HR 3.3, 95% CI: 151-7.1)( P=0.041, HR 3.1, 95% CI: 1.19.3) respectively. RUNX3 overexpression, CD4 negativity and presence of HLA/DR class II were significantly associated with the favorable cytogenetic risk group P=0.044, P=0.018 and P=0.011 respectively. The presence of HLA/DR on AML blasts indicated a better OS but not significant. The presence of inv(16) was mostly have down regulation for RUNX3(67%).
Conclusion
In conclusion, RUNX 1, 2 and 3 showed overexpression but IHH and SHH displayed down regulation comparing with normal control. The strongest positive correlation was found between IHH and SHH expression. IHH was positively correlated to RUNX2 only. An independent positive impact of RUNX3 overexpression and higher hemoglobin on OS in Egyptian adult non M3-AML patients could make RUNX3 a promising prognostic biomarker for Acute Myeloid Leukemia.