Apoptosis and immaturity in acute myeloid leukemia

The primary cause of treatment failures in acute myeloid leukemia ( AML) is the emergence of both resistant disease and early relapse. Among the most frequent agents of these phenomena are defects in the mitochondrial-mediated apoptotic pathway. This pathway is regulated by bcl-2 family of anti-apoptotic ( bcl-2, bcl-xl, mcl-1) and pro-apoptotic proteins ( bax, bad, bak). In particular, bcl-2 dimerizes with several members of bcl-2 family of proteins, altering the threshold of cell death. The flow cytometric quantitative measurement of bcl-2 and bax expression for the determination of bax/bcl-2 ratio provided crucial clinical information in AML: in our hands, lower bax/bcl-2 ratio conferred a very poor prognosis with decreased rates of complete remission ( CR) and overall survival ( OS). Moreover, striking correlations were found between lower bax/bcl-2 ratio and higher progenitor marker expression, such as CD34, CD117 and CD133 antigens, confirming the link between this apoptotic index and the maturation pathways. However, the capacity of bax/bcl-2 ratio to clearly identify patients with different prognosis with regard to CR and OS within the CD34+, CD117+ and CD133+ subgroups implies that other mechanisms, such as proliferation and/or cell cycle dysregulation may be involved to explain its clinical significance. Finally, small molecules that target both the receptor- and mitochondrial-mediated pathway of apoptosis are providing encouraging results in patients with relapsed and/or refractory disease ( i.e. CDDOMe, bcl-2 antisense oligonucleotides, CEP-701, etc), confirming the key role of apoptotic mechanisms on the outcome of AML patients.