SNP309 as predictor for sensitivity of CLL cells to the MDM2 inhibitor nutlin-3a

To the editor:

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 groups^4-6  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 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.