title: Apoptosis and immaturity in acute myeloid leukemia.
abstract: 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.
authors: Cattedra di Ematologia, Università Tor Vergata, Roma, Italy.
authors: Maria Ilaria
authors: MI
authors: Del Principe
authors: Giovanni
authors: G
authors: Del Poeta
authors: Adriano
authors: A
authors: Venditti
authors: Francesco
authors: F
authors: Buccisano
authors: Luca
authors: L
authors: Maurillo
authors: Carla
authors: C
authors: Mazzone
authors: Antonio
authors: A
authors: Bruno
authors: Benedetta
authors: B
authors: Neri
authors: Maria
authors: M
authors: Irno Consalvo
authors: Francesco
authors: F
authors: Lo Coco
authors: Sergio
authors: S
authors: Amadori
mesh_terms: D000208:Acute Disease; D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000473:pathology*; D024101:Mitochondrial Proteins / Q000502:physiology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D024101:Mitochondrial Proteins; D019253:Proto-Oncogene Proteins c-bcl-2