Inducible deletion of CDK4 and CDK6 - deciphering CDK4/6 inhibitor effects in the hematopoietic system

Haematologica. 2021 Oct 1;106(10):2624-2632. doi: 10.3324/haematol.2020.256313.


Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors are considered a breakthrough in cancer therapy. Currently approved for breast cancer treatment, CDK4/6 inhibitors are extensively tested in other cancer subtypes. Frequently observed side effects include hematological abnormalities such as reduced numbers of neutrophils, erythroid cells and platelets that are associated with anemia, bleeding and a higher risk of infections. In order to understand whether the adverse effects within the hematopoietic system are related to CDK4 or CDK6 we generated transgenic mice that lack either CDK4 or CDK6 in adult hematopoiesis. Anemia and perturbed erythroid differentiation are associated with the absence of CDK6 but did not manifest in CDK4- deficient mice. Total CDK6 knockout mice accumulate the most dormant fraction of hematopoietic stem cells due to an impaired exit of the quiescent state. We recapitulated this finding by deleting CDK6 in adult hematopoiesis. In addition, unlike total CDK6 knockout, all stem cell fractions were affected and increased in numbers. The deletion of CDK6 was also accompanied by neutropenia which is frequently seen in patients receiving CDK4/6 inhibitors. This was not the case in the absence of CDK4; CDK4 deficiency resulted in elevated numbers of myeloid progenitors without translating into numeric changes of differentiated myeloid cells. By using Cdk4fl/fl and Cdk6fl/fl mice we assign side effects of CDK4/6 inhibitors predominantly to the absence of CDK6. These mice represent a novel and powerful tool that will enable to study the distinct functions of CDK4 and CDK6 in a tissue-dependent manner.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms*
  • Cyclin-Dependent Kinase 4* / genetics
  • Cyclin-Dependent Kinase 6* / genetics
  • Female
  • Gene Deletion
  • Hematopoiesis / genetics
  • Hematopoietic Stem Cells*
  • Mice
  • Mice, Knockout
  • Mice, Transgenic


  • Cdk4 protein, mouse
  • Cdk6 protein, mouse
  • Cyclin-Dependent Kinase 4
  • Cyclin-Dependent Kinase 6

Grants and funding

Funding: This work has received funding from the European Research Council under the European Union’s Horizon 2020 research and innovation program grant agreement 694354 (VS) and was also supported by the Austrian Science Fund grant SFB-F6107 and F6101.