We appreciate the rationale for testing MDM2 single nucleotide polymorphism (SNP) 309 status in chronic lymphocytic leukemia (CLL) as a potential predictor of sensitivity to murine double minute 2 (MDM2) inhibitor treatment and for progressive CLL1 as outlined in the letter to the editor by Seyfried et al. We did indeed test our published cohort of CLL cases for SNP309 status using genomic polymerase chain reaction on DNA derived from fluorescence-activated cell sorted CD19+ cells.2 In total, 87 samples without known p53 aberrations (wt p53 exon 5-9 sequence and preserved p53 induction in response to MDM2 inhibitor treatment) were genotyped.
As demonstrated in Figure 1, we found no association between MDM2 inhibitor concentration that resulted in 50% apoptosis (IC50 values) and MDM2-SNP309 genotype (allele status TT, TG, or GG). Thus, based on this data in CLL, MDM2 protein levels do not seem to affect MDM2 inhibitor sensitivity.
Display of mean IC50 values for MDM2-inhibitor-induced CLL apoptosis/necrosis. IC50 values for the MDM2 inhibitors MI-63 (A) and nutlin3 (B): MDM2 inhibitor-mediated CLL cell apoptosis was measured in purified CD19+ cells as described.2 SNP309 genotyping was done using genomic polymerase chain reaction across MDM2 SNP309. Displayed are mean IC50 values grouped by MDM2 SNP309 genotype (TT, TG, GG) and 95% confidence bars.
Display of mean IC50 values for MDM2-inhibitor-induced CLL apoptosis/necrosis. IC50 values for the MDM2 inhibitors MI-63 (A) and nutlin3 (B): MDM2 inhibitor-mediated CLL cell apoptosis was measured in purified CD19+ cells as described.2 SNP309 genotyping was done using genomic polymerase chain reaction across MDM2 SNP309. Displayed are mean IC50 values grouped by MDM2 SNP309 genotype (TT, TG, GG) and 95% confidence bars.
Authorship
Conflict-of-interest disclosure: The author declares no competing financial interests.
Correspondence: Sami N. Malek, 4312 Cancer Center, 1500 E Medical Center Drive, University of Michigan, Ann Arbor, MI 48109-0640; e-mail: smalek@med.umich.edu.
