Apoptosis and immaturity in acute myeloid leukemia

Maria Ilaria Del Principe, Giovanni Del Poeta, Adriano Venditti, Francesco Buccisano, Luca Maurillo, Carla Mazzone, Antonio Bruno, Benedetta Neri, Maria Irno Consalvo, Francesco Lo Coco, Sergio Amadori

Research output: Contribution to journalArticle

Abstract

The primary cause of treatment failures in acute mycloid 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.

Original languageEnglish
Pages (from-to)25-34
Number of pages10
JournalHematology
Volume10
Issue number1
DOIs
Publication statusPublished - Feb 2005

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Keywords

  • Acute myeloid leukemia
  • Apoptosis
  • Immaturity
  • Prognosis
  • Targeted therapies

ASJC Scopus subject areas

  • Hematology

Cite this

Del Principe, M. I., Del Poeta, G., Venditti, A., Buccisano, F., Maurillo, L., Mazzone, C., Bruno, A., Neri, B., Consalvo, M. I., Lo Coco, F., & Amadori, S. (2005). Apoptosis and immaturity in acute myeloid leukemia. Hematology, 10(1), 25-34. https://doi.org/10.1080/10245330400020454