Overexpression of Bcl2 protein predicts chemoresistance in acute myeloid leukemia: Its correlation with FLT3

Abstract

Potential prognostic biomarkers in acute myeloid leukemia (AML) can be identified by understanding the cellular pathway and molecular changes underlying leukemogenesis. Deregulation of apoptosis is one of the important features of AML and to understand the molecular mechanism underlying apoptosis and its contribution to tumor progression, this study aimed to evaluate anti-apoptotic Bcl2 protein expression in AML and correlate with FLT3 parameters for their role in prognosis of disease.Bcl2 and FLT3 protein expression was quantified by flow cytometry on leukemic blasts in total 174 de novo AML, myelodysplastic syndrome (MDS) and aplastic anemia patients. FLT3 internal tandem duplication (ITD), Tyrosine kinase domain (TKD) point mutations and quantification of mRNA level was carried out using PCR and RT-PCR methods.The incidence of Bcl2 positivity was 71% in AML patients. Bcl2 positivity was significantly associated with CD34+ and CD117+ AML. Bcl2 positivity tended to be associated with reduced DFS while Bcl2 positivity with FLT3 protein positivity was significantly associated with reduced DFS. In multivariate analysis, Bcl2+ and combined Bcl2+/FLT3 protein+ along with high WBC count emerged as poor prognostic factors for reduced DFS and high blast count for predicting reduced OS. In MDS patients, the incidence of Bcl2 expression was high while in aplastic anemia patients, incidence of Bcl2 expression was low.Patients with Bcl2 and FLT3 protein positivity showed significantly reduced DFS suggesting parallel role of these proteins in imparting chemoresistance to the leukemic cells.

Polymorphism in apoptotic BAX (-248G>A) gene but not in anti-apoptotic BCL2 (-938C>A) gene and its protein and mRNA expression are associated with cervical intraepithelial neoplasia

“…In a previous study [21], we evaluated the presence of BCL2 and BAX-expressing cells in cervical lesions, according the degree of lesions, and BCL2 expression was observed mainly in HSIL women when compared with LSIL and control groups, favoring carcinogenesis. In accordance, BCL2 expression was associated with decreased survival in leukemia and prostate cancer [28,29], whereas in colorectal [30,31] and breast cancer, it was related to favorable outcome.…”

Aurora A and NF-κB Survival Pathway Drive Chemoresistance in Acute Myeloid Leukemia via the TRAF-Interacting Protein TIFA

“…Recent evidences attribute a growing number of malignancies to aberrant activation of NF-kB that cross talks with other signaling molecules and pathways (6), thus it is considered a risk factor for poor prognosis in several types of cancer including leukemia (7). In agreement, constitutively activated NF-kB was shown to protect tumor cells from apoptotic stimuli and promote their resistance to chemotherapies and ionizing radiation (8), presumably through transcriptional activation of antiapoptotic/prosurvival factors Bcl-2 and Bcl-X L (9). In line with this notion, the role of NF-kB in leukemogenesis has also been addressed for AML (10), and the inhibition of NF-kB reattains chemosensitivity in this hematopoietic malignancy presumably due to attenuated prosurvival responses and activated proapoptotic signals (11).…”

“…Constitutive NF-kB signaling may pathogenically transactivate inflammatory cytokines and prosurvival factors resulting in deregulated expansion of MDS bone marrow progenitors, while inhibition of NF-kB activity induces apoptosis in normal and MDS bone marrow precursors (43). Consequently, Bcl-2 and Bcl-X L are considered indicators for chemoresistance in myeloid malignancies including AML (9,12,44,45). Because TIFA regulates NF-kB-driven innate immunity (30), the leukemogenic role of TIFA we observed in AML is more likely through the NF-kB-dependent antiapoptotic/prosurvival pathways.…”

TIFA Promotes Cell Survival and Migration in Lung Adenocarcinoma

“…An increasing number of recent evidence indicates that NF-κB is aberrantly activated and cross-talks with other signaling molecules and pathways in chronic inflammation and a spectrum of malignancies [24]. Consistently, the phosphorylation of p65 in cancer cells was shown to protect tumor cells from apoptosis and increase their resistance to chemotherapy and ionizing radiation through regulation of the balance between pro-apoptotic and antiapoptotic factors [25,26]. In line with this concept, the role of NF-κB and its downstream molecules in the modulation of lung cancer cell cycle and survival was explored in this study.…”