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

Abstract

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.

T Cell-Intrinsic CDK6 Is Dispensable for Anti-Viral and Anti-Tumor Responses In Vivo

“…It remains however unclear, whether the effects observed in CD8+ T cells are cell-intrinsic or caused by changes in other cell types. To address that, we generated mice with a T cell-specific deletion of CDK6 by crossing Cdk6 fl/fl ( 29 ) to CD4-Cre mice ( 30 ). In this mouse model floxed genes are deleted at the CD4/CD8 double-positive (DP) thymocyte stage and all T cell populations are affected ( 45 ).…”

“…Wild-type (C57BL/6), Cdk6 -/- (C57BL/6 background) ( 5 ) and Cdk6 K43M (C57BL/6 background) ( 7 ) were bred in house. The T cell-specific mouse model was obtained by crossing Cdk6 fl/fl [C57BL/6N-Cdk6 tm1c(EUCOMM)Wtsi /Tcp ( 29 )] to CD4-Cre mice [B6;D2-Tg(Cd4-cre)1Cwi/CwiCnrm ( 30 ), bred on C57BL/6 background and kindly provided by Wilfried Ellmeier, Institute of Immunology, MedUni Vienna]. All mice were maintained under specific pathogen-free conditions at the University of Veterinary Medicine Vienna according to Federation for Laboratory Animal Science Associations (FELASA) guidelines (2014).…”

Beyond “to divide or not to divide”: Kinetics matters in hematopoietic stem cells

“…However, Cdk6 is strictly necessary for HSC exit from quiescence and activation under stress conditions. Cdk6 action during this transition cannot be compensated by Cdk4, as demonstrated with constitutive [47] and conditional Cdk6 knock-out models [48].…”

Clinical and Genotypic Insights Into Higher Prevalence of Palbociclib Associated Neutropenia in Asian Patients

“…Studies have proposed that CDK6 may be the main culprit for CDK4/6i-induced neutropenia, as mouse models suggest deletion of CDK6, but not CDK4, results in neutropenia. 52 In vitro data suggest ribociclib and abemaciclib, 53 , 54 but not Palbociclib, 55 , 56 to be more selective of CDK4 over CDK6. One study proposed that different CDK4/6is demonstrate variable efficacy in cell lines with CDK4 or CDK6 dependence, 57 raising the tantalizing idea that CDK4, and CDK6 are not “equal” as determinants to efficacy.…”