High GLI-1 Expression is a Reliable Indicator of Bad Prognosis in Newly Diagnosed Acute Leukemia Patients.

PURPOSE: To explore the expression and prognostic significance of Hedgehog signaling transcription factor GLI-1 in newly diagnosed acute myeloid leukemia (AML) patients. METHODS: Clinical specimens were obtained from 46 recently diagnosed AML patients. Real-time qPCR was used to measure the GLI-1 mRNA expression in bone marrow mononuclear cells.Also, the relationship between GLI-1 mRNA levels and clinical variables and prognostic variables was assessed. RESULTS: GLI-1 was overexpressed in the bone marrow samples of our patients. GLI-1mRNA expression did not differ significantly across different age groups, between both sexes, or between different FAB subtypes (P = 0.882, P = 0.246, and P = 0.890, respectively). GLI-1 expression varied significantly in different risk categories, with the greatest levels observed in 11 patients with poor risk (24.6 versus 22.7) compared to intermediate risk (5.2 versus 3.9; P = 0.006) and favorable risk (4.2 versus 3; P = 0.001). Comparing patients with the wild FLT3 allele to those with the mutant one, GLI-1 gene levels were considerably greater in those with the mutant allele of FLT3.Following induction chemotherapy, the levels of GLI-1 mRNA were significantly higher in 22 patients who did not experience complete remission (CR) diagnosed with de novo non-acute promyelocytic leukemia (APL) compared to 17 patients who did (P = 0.017). Significantly greater levels of expression were observed in each category of the patients with favorable risk; wild FLT3 allele (P = 0.033) and CR failure P = 0.005). CONCLUSION: GLI-1 overexpression is a risk factor for poor prognosis and could be a novel therapeutic target for AML.

SMYD2 Expression: Its Relationship to Cytogenetic and Prognosis in a Newly Diagnosed Childhood B-Acute Lymphoblastic Leukemia.

BACKGROUND: The SMYD2 gene adjusts lysine residues on histones and non-histone proteins such as transcription factors, signaling kinases, and cell cycle regulators affecting the cell fate and other genes' expression. As it acts as an oncogene, SMYD2's expression levels may affect tumor progression. In this prospective study, our main aim was to determine the association of SMYD2 gene expression with the prognostic parameters of childhood B-acute lymphoblastic leukemia (B-ALL) and evaluate its influence on disease prognosis. METHODS: SMYD2 gene expression was measured in the peripheral blood (PB) samples of 116 newly diagnosed B-ALL patients and 23 controls using real-time polymerase chain reaction (RT-PCR). RESULTS: SMYD2 expression was significantly higher in the childhood B-ALL patients compared with the control group, p-value < 0.001. The patients with unfavorable rather than favorable structural chromosomal abnormalities had significantly higher SMYD2 mRNA levels, p < 0.001. SMYD2 expression levels were positively correlated with total leucocytes count (r = 0.206, p-value = 0.027) and peripheral blood blasts (r = 0.225, p-value = 0.015). There was a statistical difference between the B-ALL cases with high versus low SMYD2 levels regarding translocation (t12; 21), p-value = 0.015. Cox regression analysis identified the increased levels of SMYD2 as an independent prognostic factor affecting both OS and DFS. CONCLUSIONS: The SMYD2 gene plays a vital oncogenic role in childhood B-ALL. The association of high SMYD2 levels with unfavorable cytogenetics in childhood B-ALL may be helpful in understanding the relationship between structural chromosomal abnormalities and epigenetic dysregulation. High SMYD2 levels may be useful in the prediction of prognosis in childhood B-ALL.

Promoter methylation might shift the balance of Galectin-3 & 12 expression in de novo adult acute myeloid leukemia patients.

Acute myeloid leukemia (AML) was reported as the most common type of leukemia among adults. Galectins constitute a family of galactose-binding proteins reported to play a critical role in many malignancies including AML. Galectin-3 and -12 are members of the mammalian galectin family. To understand the contribution of galectin-3 and -12 promoter methylation to their expression, we performed bisulfite methylation-specific (MSP)-PCR and bisulfite genomic sequencing (BGS) of primary leukemic cells in patients with de novo AML before receiving any therapy. Here, we show a significant loss of LGALS12 gene expression in association with promoter methylation. The lowest degree of expression was found in the methylated (M) group while the highest degree was in the unmethylated (U) group and the partially methylated (P) group expression lies in between. This was not the case with galectin-3 in our cohort unless the CpG sites analyzed were outside the frame of the studied fragment. We were also able to identify four CpG sites (CpG number 1, 5, 7& 8) in the promoter region of galectin-12; these sites must be unmethylated so that expression can be induced. As far as the authors know, these findings were not previously concluded in earlier studies.

Clinical significance of EVI-1 gene expression and aberrations in patient with de-novo acute myeloid and acute lymphoid leukemia.

BACKGROUND: Acute leukemia is a common health problem in adults and children, however its exact molecular etiology is still unclear. METHODS: The expression of EVI-1 was assessed in the bone marrow of 178 de-novo acute leukemia patients (101 AML, 71 ALL and 6 MPAL), compared to 40 control subjects. EVI-1 gene aberrations were also assessed in 69 AML patients using Fluorescence in situ hybridization (FISH) technique. RESULTS: The expression of EVI-1 was significantly lower in ALL patients compared to control [0.177 (0.002-15.189) vs 0.953 (0.179-1.68); respectively, P = 0.009]. There was no significant difference between AML patients and control group [0.150 (0.0-641) vs 0.953 (0.179-1.68); respectively, P = 0.082]. The sensitivity, specificity, AUC of EVI-1 in ALL were (80.3 %, 60 % and 0.778; respectively, P = 0.009), and (67.3 %, 60 %, 0.667; respectively P = 0.082) in AML patients. One patient showed EVI-1 gene rearrangement in a complex karyotype and four patients showed EVI-1 amplification in hyperdiploid karyotypes. All patients with BCR-ABL fusion were EVI-1 over-expressers (P = 0.010). AML patients with EVI-1 low expression were positively associated with t(8;21)(q22;q22)RUNX1:RUNX1T1 fusion, favorable recurrent translocation, and low genetic risk (P = 0.037, P = 0.023, and P = 0.013; respectively). There was a significant association between low EVI-1 expression and prolonged overall survival (OS) in AML patients, while there was no significant association with the disease-free survival (DFS) (P = 0.048 and P = 0.419). There was no significant impact of EVI-1 expression on OS and DFS rates in ALL patients. CONCLUSION: EVI-1 expression could be a helpful diagnostic, prognostic, and predictive biomarker for acute leukemia especially in AML.

The prognostic role of C-KIT, TET1 and TET2 gene expression in Acute Myeloid Leukemia.

AIM: was to assess the role of C-KIT, TET1 and TET2 expression in the diagnosis and prognosis of acute myeloblastic leukemia (AML). METHODS: The expression levels of C-KIT, TET1 and TET2 were assessed in the bone marrow (BM) aspirate of 152 AML patients compared to 20 healthy control using quantitative real-time polymerase chain reaction (qRT-PCR). Data were correlated with the clinico-pathological features of the patients, response to treatment, disease-free survival (DFS), and overall survival (OS) rates. RESULTS: C-KIT, TET1 and TET2 were significantly upregulated in AML patients [0.25 (0-11.6), 0.0113 (0-3.301), and 0.07 (0-4); respectively], compared to the control group [0.013 (0.005-0.250), P < 0.001, 0.001 (0-0.006), P < 0.001, and 0.02 (0.008-0.055), P = 0.019; respectively]. The sensitivity, specificity, and area under curve of of C-KIT were (48.7%, 100%, 0.855; respectively, P = 0.001), and that of TET1 were (63.4%, 100%, 0.897; respectively, P = 0.001), while that of TET2 were (56.8%, 100%, 0.766; respectively, P = 0.019). When combining the three markers, the sensitivity was 77.5%, however it reached the highest sensitivity (78.6%) and specificity (100%) when combining both c-KIT + TET1 together for the diagnosis of AML. C-KIT overexpression associated with shorter DFS (P = 0.05) and increased incidence of relapse (P = 0.019). Lymph nodes involvement [HR = 2.200, P = 0.005] is an independent risk factor for shorter OS rate of AML patients. Increased BM blast % [HR = 7.768, P = 0.002], and FLT3-ITD mutation [HR = 2.989, P = 0.032] are independent risk factors for shorter DSF rate of the patients. CONCLUSION: C-KIT, TET1, and TET2 could be used as possible useful biomarkers for the diagnosis of AML.

Impact of circulating miRNA-373 on breast cancer diagnosis through targeting VEGF and cyclin D1 genes.

BACKGROUND: Breast cancer (BC) is the common primary tumor among females. Hence, there is an urgent need to improve the early prediction and diagnosis of BC. For that reason, the object of the current study is to analyze the expression levels of miRNA-373 and its target genes including vascular endothelial growth factor (VEGF) and cyclin D1 in women with BC. RESULTS: Upregulation of miRNA-373 and its target genes was observed in BC patients followed by patients with benign breast lesions compared to downregulation in controls. There was a significant association between the expression level of miRNA-373 and all clinical features. The same associations were observed between its target genes and all clinico-pathological features except hormonal status. The correlation between miRNA-373 and both genes was significant. CONCLUSIONS: Our results prove that miRNA-373, as an oncomir, would be a vital biomarker for BC diagnosis and prognosis by targeting both VEGF and cyclin D1.