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From www.bloodjournal.org by guest on August 3, 2017. For personal use only. 2168 BLOOD, 1 SEPTEMBER 2008 䡠 VOLUME 112, NUMBER 5 CORRESPONDENCE To the editor: SNP309 as predictor for sensitivity of CLL cells to the MDM2 inhibitor nutlin-3a From a recent comprehensive genomic analysis focusing on loss of heterozygosity, p53 deletion/mutation, and other chronic lymphocytic leukemia (CLL)–specific risk parameters, Saddler et al concluded that the p53 status is the major determinant of response to murine double minute 2 (MDM2) inhibitors in chronic lymphocytic leukemia.1 They found that sensitivity of CLL cells to MDM2 inhibitors was significantly dependent on functional p53, but was influenced neither by the other genetic aberrations tested (del11q, trisomy12, del13q14), by Ig VH mutational status, or by Zap-70 expression.1 Their subgroup analysis of CLL cases without p53 aberrations unexpectedly revealed that chemonaive patients who displayed high sensitivity to MDM2-inhibitor treatment in vitro showed a significantly reduced treatment-free survival (TFS) compared with patients with relatively less sensitive CLL cells.1 The molecular reasons for this observation, however, could not be elucidated in that study. We recently analyzed the role of a single nucleotide polymorphism (SNP) at position 309 in the promoter region of MDM22 that has been reported to increase expression of MDM2 and to attenuate p53 function in B-cell CLL (B-CLL).3 We could demonstrate a significant correlation between the SNP309 genotype and overall survival (OS) and TFS but not with incidence or onset of B-CLL.2 It was shown earlier by 3 independent groups4-6 and now confirmed by Saddler et al1 that the MDM2 inhibitor nutlin-3a efficiently induces apoptosis in B-CLL cells in vitro. In our present study we could also confirm its proapoptotic activity in B-CLL cells in general (Figure 1A), which was higher compared with B cells from healthy donors (Figure 1B). Kojima et al initially reported that MDM2 overexpression is not an obstacle to nutlin-induced apoptosis.6 We therefore tested whether sensitivity of B-CLL cells was also independent of the SNP309 genotype. Interestingly, the percentages of apoptotic B-CLL Specific apoptosis [% of control] A 100 B-CLL T/G (n=14) or G/G (n=3) T/T (n=16) B 80 P = .007 60 P = .01 P = .01 Irina Seyfried, Sebastian Hofbauer, Markus Stoecher, Richard Greil, and Inge Tinhofer This work was supported by a grant from the Paracelsus Medical University (PMU) Forschungsgesellschaft (grant no. 05/02/014 to I.S.) and by grants of the Austrian Science Foundation (to I.T.: SFB021-11) and the Province of Salzburg (to R.G. and I.T.). Conflict-of-interest disclosure: The authors declare no competing financial interests. Correspondence: Inge Tinhofer, Laboratory of Immunological and Molecular Cancer Research, Department of Hematology, Oncology, Hemostaseology, Rheumatology and Infectiology, University Hospital Salzburg, Muellner Hauptstrasse 48, 5020 Salzburg, Austria; e-mail: [email protected]. References Healthy donors T/G (n=8) T/T (n=5) P = .01 cells following nutlin-3a treatment were even significantly higher in B-CLL samples with the unfavorable SNP309 T/G or G/G genotypes (Figure 1A). Higher sensitivity of SNP309 T/G variants to nutlin-3a treatment was not specific for B-CLL cells, but also observed in CD19⫹ B cells from healthy controls (Figure 1B). Comparable with our observation, a positive correlation of MDM2 basal expression and sensitivity to nutlin-3a has also been reported recently for AML7 and human solid tumor cell lines.8 From our results it is tempting to speculate that the aggressive course of disease observed by Saddler et al in patients with high sensitivity to nutlin-3a treatment in vitro results from a higher frequency of patients with the unfavorable SNP309 T/G or G/G genotype in that patient subgroup. This could be tested easily and, if confirmed, would significantly support the value of the SNP309 genotype as prognostic factor for aggressive B-CLL as well as predictor for increased sensitivity to treatment with nutlin-3a. P = .04 1. Saddler C, Ouillette P, Kujawski L, et al. Comprehensive biomarker and genomic analysis identifies p53 status as the major determinant of response to MDM2 inhibitors in chronic lymphocytic leukemia. Blood. 2008;111:15841593. 2. Gryshchenko I, Hofbauer S, Stoecher M, et al. MDM2 SNP309 is associated with poor outcome in B-cell chronic lymphocytic leukemia. J Clin Oncol. 2008; 26:2252-2257. 3. Bond GL, Hu W, Bond EE, et al. A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans. Cell. 2004;119:591-602. 4. Coll-Mulet L, Iglesias-Serret D, Santidrian AF, et al. MDM2 antagonists activate p53 and synergize with genotoxic drugs in B-cell chronic lymphocytic leukemia cells. Blood. 2006;107:4109-4114. 5. Secchiero P, Barbarotto E, Tiribelli M, et al. Functional integrity of the p53-mediated apoptotic pathway induced by the nongenotoxic agent nutlin-3 in B-cell chronic lymphocytic leukemia (B-CLL). Blood. 2006;107: 4122-4129. 6. Kojima K, Konopleva M, McQueen T, O’Brien S, Plunkett W, Andreeff M. Mdm2 inhibitor Nutlin-3a induces p53-mediated apoptosis by transcription-dependent and transcription-independent mechanisms and may overcome Atm-mediated resistance to fludarabine in chronic lymphocytic leukemia. Blood. 2006;108: 993-1000. 7. Kojima K, Konopleva M, Samudio IJ, et al. MDM2 antagonists induce p53dependent apoptosis in AML: implications for leukemia therapy. Blood. 2005;106: 3150-3159. 8. Tovar C, Rosinski J, Filipovic Z, et al. Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy. Proc Natl Acad Sci U S A. 2006;103:1888-1893. P = .1 40 P = .1 20 0 1 2.5 5 10 1 2.5 5 10 Nutlin-3a [µmol/L] Figure 1. The SNP309 genotype influences sensitivity of B-CLL cells and B cells from healthy controls to in vitro-treatment with nutlin-3a. PBMCs from (A) B-CLL patients or (B) healthy donors with T/T, T/G or G/G SNP309 genotype were treated with increasing concentrations of nutlin-3a for 24 hours. Analysis of apoptosis in the CD19⫹CD5⫹ fraction (A, B-CLL) or CD19⫹ fraction (B, healthy controls) was performed by the annexin V–fluorescein isothiocyanate binding assay. The relative number of cells undergoing nutlin-3a-induced apoptosis are presented as the percentage of untreated control. Sample numbers within the respective genotype subgroup are indicated. From www.bloodjournal.org by guest on August 3, 2017. For personal use only. 2008 112: 2168 doi:10.1182/blood-2008-05-158634 SNP309 as predictor for sensitivity of CLL cells to the MDM2 inhibitor nutlin-3a Irina Seyfried, Sebastian Hofbauer, Markus Stoecher, Richard Greil and Inge Tinhofer Updated information and services can be found at: http://www.bloodjournal.org/content/112/5/2168.full.html Articles on similar topics can be found in the following Blood collections Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. 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