Originally published online as doi:10.1189/jlb.0408222 on June 2, 2008
Published online before print June 2, 2008
(Journal of Leukocyte Biology. 2008;84:651.)
© 2008
by Society for Leukocyte Biology
The potential role of Nutlins in the treatment of B-chronic lymphocytic leukemia (B-CLL)
Federica Corallini and
Claudio Celeghini1
Department of Biomedicine, University of Trieste, Trieste, Italy
1 Correspondence: Department of Biomedicine, University of Trieste, Via Manzoni 16, 34138 Trieste, Italy. E-mail: cceleghini{at}units.it
Key Words: apoptosis • cell cycle progression • MDM2 inhibitor • CpG oligodeoxynucleotides
In their recent study, Secchiero and collegues [1
] demonstrated that p53 is the major determinant of responsiveness to mouse double minute 2 inhibitors, such as Nutlin-3a. Of note, four different studies [2
3
4
5
] suggest that p53 immunoblotting on B-chronic lymphocytic leukemia (B-CLL) cells pre- and post-treatment with Nutlins should enter into the clinical practice to monitor the p53 status, as an aberrant p53 response to Nutlins (absence of p53 induction or unmodified, high basal levels of p53 protein) was associated to an aggressive disease course. Saddler et al. [2
] added the important information that p53 immunoblotting pre- and post-treatment with Nutlins is more informative on p53 defects, with respect to fluorescence in situ hybridization, to detect TP53 loss and p53 exon resequencing. Another important finding emerging from all of these studies [1
2
3
4
5
] was the demonstration that untreated patients that displayed high sensitivity to treatment ex vivo with Nutlins progressed significantly more rapidly and required therapy earlier than patients with relatively less-sensitive CLL cells. Although it is recognized that a considerable heterogeneity characterizes the in vitro survival of B-CLL samples, it is noteworthy that a previous study has demonstrated that the spontaneous apoptosis of B-CLL cells in vitro is significantly higher in samples with poor prognosis cytogenetics [6
]. In line with these data challenging the traditional view that B-CLL disease derives from an inherent defect in apoptosis, it has been demonstrated that between 1 x 109 and 1 x 1012 cells (0.1–1.75% of the whole B-CLL clone) are born each day in vivo in all B-CLL patients studied [7
]. Thus, a dynamic interplay between birth (cell proliferation) and death characterizes B-CLL with higher birth rates (birth >0.35% of the clone per day) associated to disease progression [7
]. Moreover, the group of Efremov [8
] has demonstrated recently that B-CLL with a poor prognosis displays increased proliferation also in vitro in response to TLR9 engagement by synthetic CpG oligodeoxynucleotides. This assay—the same used by Secchiero et al. [1
] in their study recently published in Journal of Leukocyte Biology—offers the possibility to analyze multiple parameters, such as proliferation, apoptosis, and markers of immune activation [1
, 6
]. Thus, Nutlins are potentially efficacious, not only in inducing B-CLL apoptosis [1
2
3
4
5
] but also in restraining proliferation of p53 B-CLL cells obtained from patients with a relevant, negative prognostic marker, such as Zap-70high levels [9
]. In light of the high proliferative activity of aggressive B-CLL [7
], in a therapeutic perspective, the cytostatic activity of Nutlins might be as important as their proapoptotic activity. Considering the poor prognosis of B-CLL patients with high-risk disease, despite improvements in response rates using chemoimmunotherapy combinations [10
], we believe that use of Nutlins alone or in combination with currently available therapeutic regimens will represent one important approach to ameliorate the therapeutic outcome in the vast majority of patients with wild-type p53 B-CLL.
Received April 2, 2008;
revised April 2, 2008;
accepted April 18, 2008.
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