Date Published: September 14, 2012
Publisher: Hindawi Publishing Corporation
Author(s): Flora Tzifi, Christina Economopoulou, Dimitrios Gourgiotis, Alexandros Ardavanis, Sotirios Papageorgiou, Andreas Scorilas.
The disturbance of apoptosis molecular signaling pathways is involved in carcinogenesis. BCL2 family of proteins is the hallmark of apoptosis regulation. In the last decade, new members of BCL2 gene family were discovered and cloned and were found to be differentially expressed in many types of cancer. BCL2 protein family, through its role in regulation of apoptotic pathways, is possibly related to cancer pathophysiology and resistance to conventional chemotherapy. It is well known that leukemias are haematopoietic malignancies characterized by biological diversity, varied cytogenetics, different immunophenotype profiles, and diverse outcome. Current research focuses on the prognostic impact and specific role of these proteins in the pathogenesis of leukemias. The understanding of the molecular pathways that participate in the biology of leukemias may lead to the design of new therapies which may improve patients’ survival. In the present paper, we describe current knowledge on the role of BCL2 apoptosis regulator proteins in acute and chronic leukemias.
Apoptosis, or programmed cell death, is a cell-suicide program, distinct from necrosis, which is activated in physiological processes such as tissue development and differentiation as well as in pathophysiological conditions. The term is used to describe the situation in which a cell actively pursues a course toward death upon receiving certain stimuli. The morphological changes of apoptosis found in most cell types include nuclear pyknosis, DNA fragmentation and chromatin condensation, cytoskeleton destruction, membrane blebbing, and eventually the formation of membrane apoptotic bodies, which are phagocytosed by macrophages and other cells without promoting inflammatory response . The mechanism of apoptosis is evolutionarily conserved and is executed by a family of proteins, called caspases. Caspases are cysteine proteases that are cleaved after an Asp residue in their substrates. They are synthesized as latent zymogenes and activated by proteolytic cleavage; their activation is mainly regulated by the BCL2 family proteins [2–4].
Mammalian BCL2 protein family consists of at least 30 related proteins, characterized by the presence of up to four relatively short sequence motifs (less than 20 amino acid residues in length) termed BCL2 homology (BH) domains [17–21]. BCL2 family is divided into three different subclasses based on structural and functional features.
A number of studies have linked impaired apoptosis and de-regulation of BCL2 gene family with the pathogenesis and treatment failure in ALL. A recent study  indicated a high frequency of BCL2 mRNA overexpression and a relatively low frequency of BAX mRNA overexpression in ALL and AML, suggesting that altered transcription of these genes may be involved in leukemogenesis. Moreover, BCL2 expression in neoplastic cells from patients with precursor B-ALL, typical ALL and atypical ALL was found to be aberrant in 84%, 77%, and 75% of the cases, respectively, consistent with a diverse expression of BCL2 in the different types of ALL according to the stage of B-cell maturation. . In other words, abnormal BCL2 gene expression seems to influence the survival capacity of B-cell progenitors and contribute to leukemogenesis . Additionally, Aref et al.  showed that the expression of BCL2 was higher in patients with ALL as compared to controls. Although there is a higher expression of BCL2 in ALL patients, clinical studies failed to correlate this with survival. Sahu and Das  found that there was no correlation between BCL2 expression and overall survival. Another study by Campos et al. led to similar results: high levels of BCL2 were not associated with clinical or biological characteristics in adult patients with ALL (survival of leukemic cells, outcome after intensive chemotherapy) . Although ALL patients that responded to induction chemotherapy had lower BCL2 expression compared to the nonresponders, no correlation between BCL2 expression and the outcome was found.
BCL2 gene family is overexpressed in AML and seems to play an important role not only in disease pathogenesis but also in resistance to chemotherapy. The importance of BCL2 family members in AML is indicated by the expression of BCL2, BCL2L12, BCL-XL, and BAD in leukemic CD34+ cells, whereas normal promyelocytes (in non-APL AML cases) (CD34-CD33+) lack BCL2 and BCL-XL expression. A low BCL2/BAX ratio is found in >20% of CD34+ cells, in M0/MI FAB subtypes, and in those patients with poor prognosis karyotype. Leukemic promyelocytes with the phenotype CD34+CD33-CD13—express only BCL-XL protein and not BCL2 [9, 59]. Moreover, the enhanced expression of BCL2 in CD34+ cells offers them a survival advantage and resistance to chemotherapy . Finally, BCL2 expression plays an important role in maintaining a favorable antiapoptotic microenvironment for the survival of AML blasts. In vitro studies show that stable BCL2 protein levels reduce T-cell apoptosis and favour the survival of peripheral blood cells and malignant cells . This microenvironment also prevents T-cell activation and proliferation by inhibition of several molecules like NF-κB, c-MYC, and pRB, that enables malignant cells escape from immune surveillance .
B-cell Chronic Lymphocytic Leukemia (CLL) is characterized by the accumulation of malignant clonal CD5+ CD23+ B cells.
BCR/ABL affects a number of molecular pathways, including apoptosis. Dysregulation of the expression of BCL2 protein seems to play a role in disease progression as shown in mouse models. It is overexpressed in CML cells and acts synergistically with BCR/ABL in inducing blast crisis. BCL2 is more important than c-MYC or RAS oncoproteins in the transformation of chronic to blastic phase . In vivo studies showed that BCL2 expression is restricted to the lymphocyte and blast subpopulation cells at the chronic phase, whereas it is higher in the accelerated and the blastic phase. However, other in vivo studies show that c-MYC is more important than BCL2 protein in disease progression since (a) it is expressed in more immature cells, (b) its unregulated expression can inhibit myeloid differentiation, and (c) its levels are increased in the peripheral blood blast cell subpopulation in the accelerated and blastic phase [105, 106]. These studies also suggest that the expression of apoptosis oncoproteins such as BCL2, BAX, FAS and caspase-3 is not associated with the three different phases of CML, since no phase-related predominance of their levels was found.
Since BCL2 family proteins are pivotal regulators of apoptotic cell death and given their deregulation in acute and chronic leukemias, the concept of manipulating their function towards enhancing their antitumor effects seems a reasonable strategy in the design of antileukemic therapeutic agents.
BCL2 protein family plays an important role in regulating the cellular program of apoptosis. Normal cellular homeostasis appears to be dependent on the balance between pro- and antiapoptotic members of BCL2 family. BCL2 is overexpressed in almost all types and subtypes of leukemia, indicating the importance of this molecule in disease pathogenesis and evolution. BCL2 is the most well studied member of the family, but evidence shows that other BCL2 related family proteins like BAX and MCL-1 are important as well. More specifically, MCL-1 is related to almost all leukemias that show resistance to chemotherapy and bad prognosis. Expression levels of BCL2 and BCL2L12 were altered during apoptosis induced by widely used chemotherapeutic drugs in human leukemia cells. These molecules may not be used as disease markers in most cases, but their importance lies in (a) explaining drug chemoresistance and (b) in the effort to design new agents with a greater specificity. Further research should focus on the role of BCL2 family members in leukemogenesis. It is clear that clinical studies are only beginning to assess the expression of BCL2 family members. Further research is more than valuable in the understanding of the importance of this gene family in leukemias.