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. 2015 Jun;29(6):1437-41.
doi: 10.1038/leu.2015.10. Epub 2014 Jan 12.

CDK9 inhibition by dinaciclib potently suppresses Mcl-1 to induce durable apoptotic responses in aggressive MYC-driven B-cell lymphoma in vivo

G P Gregory  1 , S J Hogg  2 , L M Kats  2 , E Vidacs  2 , A J Baker  2 , O Gilan  3 , M Lefebure  2 , B P Martin  2 , M A Dawson  3 , R W Johnstone  2 , J Shortt  4
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CDK9 inhibition by dinaciclib potently suppresses Mcl-1 to induce durable apoptotic responses in aggressive MYC-driven B-cell lymphoma in vivo

G P Gregory et al. Leukemia. 2015 Jun.
No abstract available

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Figures

Figure 1
Figure 1
Dinaciclib potently induces apoptosis of murine Eμ-Myc and human IG-cMYC-translocated lymphomas with rapid and selective suppression of Mcl-1 transcription and protein levels. (a) Wild-type p53 (#4242) and p53-null (#3391) Eμ-Myc lymphomas were cultured in vitro with dimethylsulfoxide (DMSO) vehicle control or dinaciclib for 24 h and then analyzed using flow cytometric analysis for annexin-V/propidium iodide (PI) positivity. (b) Human IG-cMYC-translocated BL-41 and Ramos cell lines were cultured in vitro with DMSO or dinaciclib for 48 h before the analysis of annexin-V/PI positivity using flow cytometry. (c) Mcl-1 and Bcl-2 mRNA expression in lymphoma #4242 following 3-h in vitro treatment with DMSO or 20 nM dinaciclib. Transcript levels are represented as fold change compared with DMSO. NS, not significant; *P<0.0001. (d) Chromatin immunoprecipitation-PCR of Eμ-Myc lymphoma #4242 cells showing binding of phospho-RNA Pol II CTD serine 2 (pRpb1 Ser2) at the Mcl-1 locus. Error bars denote the s.e.m. from three independent primer sets across the Mcl-1 locus. (e) Eμ-Myc lymphoma #4242 was cultured in vitro for 3-h untreated or in the presence of DMSO or 20 nM dinaciclib before the preparation of lysates and immunoblotting for phospho-RNA Pol II CTD (pRpb1Ser2, pRpb1Ser5 and pRpb1Ser2/5), total Mcl-1, Bcl-2, Bcl-xL, c-Myc and HSP90 loading control. (f) Human IG-cMYC-translocated BL-41 and Ramos cell lines were cultured in vitro for 3 h in the presence of DMSO or 20 nM dinaciclib before the preparation of lysates and immunoblotting for total Mcl-1, Bcl-2, Bcl-xL, c-Myc, Tubulin and HSP90 loading controls. (g) Eμ-Myc lymphoma #4242 was transduced with murine stem cell virus expressing empty vector control or Mcl-1 and then cultured in vitro with dinaciclib for 24 h before flow cytometric analysis for annexin-V/PI positivity. **P<0.01 comparing treatments at 16 nm concentration. All graphs represent the mean±s.e.m (error bars) for three or more independent experiments.
Figure 2
Figure 2
Dinaciclib therapy prolongs the survival of mice bearing Eμ-Myc and human IG-cMYC-translocated lymphomas. (a–d) Kaplan–Meier survival curves representing cohorts of C57Bl/6 mice transplanted with representative Eμ-Myc lymphomas 3 days before the therapy commencement with 20% hydroxypropyl-beta-cyclodextran (HPBCD) vehicle or 30 mg/kg dinaciclib by intraperitoneal injection twice weekly. Gray shading denotes the period of therapy. dn, dominant negative; P<0.0001 for each experiment. The median survival for vehicle- and dinaciclib-treated mice were 12 days and not reached (#4242), 16 and 48 days (#3391), 18 and 66 days (#106) and 13 and 18 days (#4242tMcl-1), respectively. (e) Lymph nodes were harvested from cohorts of C57Bl/6 mice 1 or 4 h following a single dose of dinaciclib or 20% HPBCD, 12 days following transplantation with Eμ-Myc lymphoma #4242. Protein lysates were then prepared and separated by sodium dodecyl sulfate–polyacrylamide gel electrophoresis before immunoblotting for the indicated targets. Each lane represents protein lysate from the lymph nodes of an individual mouse. (f) Bioluminescence imaging of NOD-scid IL2Rγnull mice transplanted with human IG-cMYC-translocated BL-41.luc2 lymphoma 3 days before the commencement of the therapy with 20% HPBCD vehicle or 30 mg/kg dinaciclib by intraperitoneal injection twice weekly. Mice were imaged at 7 and 14 days post transplantation. (g) Overall survival of the mice from the experiment is described in f. Gray shading denotes the period of therapy. The median survival for vehicle and dinaciclib-treated mice were 19 and 26 days, respectively (P<0.001).
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References

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