الفهرس 
INTRODUCTION AND AIM OF THE WORKOnly 14 pages are availabe for public view
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Abstract
Acute myeloid leukemia is the most common type of acute leukemia in adults with the lowest survival rates of all leukemia types. In fact, the interesting role of the TGF-β in leukemogenesis is an important research pivot. Interestingly, resistance to homeostatic effects of TGF- β develops through decreased expression of TGF-β receptors on the cell surface or repression of TGF-signaling by oncoproteins. Surprisingly, despite the accumulating knowledge regarding TGF-ß resistance in several cancers, the mechanisms are still poorly understood.
An important TGF-β antagonist is the BAMBI that is a pseudo-receptor related to TGF-β receptor type I, but lacks an intracellular kinase domain. Hence, it acts as a decoy hampering TGF signaling. However, the expression levels and the potential clinical and prognostic role of BAMBI in AM still remain unclear.
Another important TGF-β signaling antagonist is SMAD7; an inhibitory SMAD that works in a negative feedback loop to inhibit the TGF-β signaling. However, till today its expression level in AML patients is not widely reported. Interestingly, it has been found that BAMBI forms a complex with SMAD7, so it is proposed that BAMBI and SMAD7 function synergistically to inhibit TGF-β signaling. However, their expression levels together and their correlation to cancer patients’ prognosis haven’t been widely reported clinically.
Another, interesting cancer specific target, is the TERT, that allows cells to limitlessly divide and evade apoptosis by extending chromosome telomeres which is widely known as the telomerase canonical function. However, accumulated evidence suggests that TERT may have a non-canonical telomerase-independent role in cancer through transcriptionally regulating some genes. It was postulated that TERT activation can inhibit TGF-β signaling probably by telomerase independent functions through activating TGF-β signaling antagonists as BAMBI and SMAD7. However, this interesting telomerase independent activity of TERT has not been yet validated clinically in AML patients nor in any other cancer.
Thus, this study aimed to:
1- Explore BAMBI and SMAD7 expression levels in AML patients.
2- Explore the possible associations of BAMBI, SMAD7 and TERT expression levels with AML prognosis.
In order to fulfill this aim, this study was conducted on 90 subjects divided into the following groups:
I. Healthy control group (group I):
This group included 16 age and gender matched healthy adult volunteers.
II. Acute myeloid leukemia patients’ group (group II):
A total of 74 patients newly diagnosed with de-novo AML.
Then Evaluation of BAMBI, SMAD7, and TERT genes expression was determined in different groups using RT-PCR after RNA extraction using suitable reagents followed by suitable statistical analysis to gain more insights into our results.
The results of the current study can be summarized as follows:
1-The expression levels of BAMBI, SMAD7 and TERT were significantly upregulated compared to controls.
2- Patients with high expression of BAMBI had higher levels of BM blasts and serum LDH. Moreover, they showed poorer risk status, lower percentages of achieving CR as well as higher rates of both relapse and mortality, however they showed lower levels of platelets count and lower percentage of the favorable karyotype (t(8;21)/RUNX1‐RUNX1T1) compared to those having low BAMBI expression.
3- Patients with high expression of SMAD7 had higher levels of BM blasts and serum LDH. Moreover, they showed poorer risk status, lower percentages of achieving CR as well as higher rate of mortality, however they showed lower percentage of the favorable karyotype (t(8;21)/RUNX1‐RUNX1T1) compared to those having low SMAD7 expression.
4- Spearman correlation coefficient showed that there was a highly significant positive correlation between the expression levels of BAMBI, SMAD7 and TERT together.
5- The Kaplan–Meier analysis and the log‐rank test were used to analyze the effect of the studied genes expression on EFS/OS in AML patients. Patients with high BAMBI, SMAD7 and TERT expression had significantly shorter EFS and OS than those having low expression levels of those genes.
6- Univariate and multivariate Cox regression analyses were performed to determine the independent risk factors affecting EFS and OS. Univariate analysis showed that age, risk status, CR achievement, BAMBI, SMAD7 and TERT expression levels were independent adverse prognostic factors for both EFS and OS. Interestingly, multivariate analysis revealed that only BAMBI expression remained an independent prognostic factor for OS in AML patients, where high BAMBI expression was associated with poor OS (HR=8.853, p=0.001) compared to low BAMBI expression.
In conclusion, our study is the first to investigate the association between BAMBI, SMAD7 and TERT expression levels in AML pathogenesis. We first demonstrated that high expression of BAMBI can predict adverse prognosis in AML and may thus guide treatment decisions for AML. Additionally, we demonstrated that BAMBI and SMAD7 levels were strongly positively correlated to each other and were found to be highly upregulated in AML patients with poorer risk status and in those failing CR after induction therapy as well as those who died.
Moreover, Kaplan Meier analysis revealed that patients with higher BAMBI, SMAD7 and TERT expression had shorter EFS and OS than those having low expression levels of those genes. Finally, our data showed that BAMBI could be considered as an independent prognostic factor for OS in AML patients. These data collectively indicate that BAMBI may serve as a novel promising prognostic marker in AML and that there is some sort of interplay between BAMBI and SMAD7 in AML pathogenesis and prognosis most probably involving a TERT non-canonical impact.