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 language | English |
|---|---|
| Pages (from-to) | 25-34 |
| Number of pages | 10 |
| Journal | Hematology |
| Volume | 10 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Feb 2005 |
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Keywords
- Acute myeloid leukemia
- Apoptosis
- Immaturity
- Prognosis
- Targeted therapies
ASJC Scopus subject areas
- Hematology
Cite this
Apoptosis and immaturity in acute myeloid leukemia. / Del Principe, Maria Ilaria; Del Poeta, Giovanni; Venditti, Adriano; Buccisano, Francesco; Maurillo, Luca; Mazzone, Carla; Bruno, Antonio; Neri, Benedetta; Consalvo, Maria Irno; Lo Coco, Francesco; Amadori, Sergio.
In: Hematology, Vol. 10, No. 1, 02.2005, p. 25-34.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Apoptosis and immaturity in acute myeloid leukemia
AU - Del Principe, Maria Ilaria
AU - Del Poeta, Giovanni
AU - Venditti, Adriano
AU - Buccisano, Francesco
AU - Maurillo, Luca
AU - Mazzone, Carla
AU - Bruno, Antonio
AU - Neri, Benedetta
AU - Consalvo, Maria Irno
AU - Lo Coco, Francesco
AU - Amadori, Sergio
PY - 2005/2
Y1 - 2005/2
N2 - 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.
AB - 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.
KW - Acute myeloid leukemia
KW - Apoptosis
KW - Immaturity
KW - Prognosis
KW - Targeted therapies
UR - http://www.scopus.com/inward/record.url?scp=23244458293&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=23244458293&partnerID=8YFLogxK
U2 - 10.1080/10245330400020454
DO - 10.1080/10245330400020454
M3 - Article
VL - 10
SP - 25
EP - 34
JO - Hematology
JF - Hematology
SN - 1024-5332
IS - 1
ER -