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B. Maurer et al.
changes in the myeloid-primed progenitor pool in Cdk6D/D BM 3 weeks after Cdk6 deletion (Figure 4A; Online Supplementary Figure S4A and B), the numbers of CD11b+Gr1hi differentiated granulocytes were drastically reduced in BM (Figure 4C; Online Supplementary Figure S4C) and blood (Online Supplementary Figure S4E) of Cdk6D/D mice, reminiscent to observations in Cdk6-/- mice. This difference was less pronounced 6 weeks after Cdk6 deletion (Online Supplementary Figure S4H). The frequent pronounced drop in white blood cell (WBC) numbers that is observed in patients upon long-term CDK4/6 inhibitor- treatment30 was not recapitulated in our experimental set- ting (Online Supplementary Figure S4F).
Discussion
The close homologues CDK4 and CDK6 play crucial roles in cell cycle progression and represent promising therapeutic targets in cancer. Inhibitors targeting both kinases have been approved for breast cancer treatment and are investigated in clinical trials for the treatment of additional solid and hematological malignancies. CDK4/6 inhibitor-associated side effects manifest primarily in the hematopoietic system and include anemia, neutropenia and lymphopenia.28,29,38 As attempts are ongoing to devel- op CDK inhibitors that will more specifically target indi- vidual CDK it is important to attribute side effects to either CDK4 or CDK6. We analyzed novel mouse models
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Figure 2. Cdk6Δ/Δ mice are anemic with compensatory upregulation of erythro- cytes in the bone marrow. Analysis was performed 3 weeks post final polyi- nosinic–polycytidylic acid (poly(I:C)) injection. (A) Number of red blood cells (RBC) in peripheral blood (n≥12 for each group (Cdk4∆/∆; Cdk6∆/∆; Cdk4/6fl/fl). (B) Percentage of Ter119+ cells in bone marrow quantified by flow cytometry (Cdk4∆/∆; Cdk6∆/∆; Cdk4/6fl/fl, n≥7/genotype). (C) Gating strategy and representa- tive flow cytometry pseudocolour plots for (D) quantification of erythroid devel- opment in the bone marrow (BM) based on CD71 and Ter119 expression from R1 to R4 (Cdk4∆/∆; Cdk6∆/∆; Cdk4/6fl/fl, n≥8/genotype). All comparisons were done with one-way ANOVA followed by Tukey's Multiple Comparison Test, *P≤0.05, **P≤0.01, ***P≤0.001, ****P≤0.0001.
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haematologica | 2021; 106(10)