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Ferrata Storti Foundation
Haematologica 2021 Volume 106(10):2624-2632
Inducible deletion of CDK4 and CDK6 – deciphering CDK4/6 inhibitor effects in the hematopoietic system
Barbara Maurer,* Tania Brandstoetter,* Sebastian Kollmann, Veronika Sexl,# and Michaela Prchal-Murphy#
Institute of Pharmacology and Toxicology, University of Veterinary Medicine, Vienna, Austria
*BM and TB contributed equally as co-first authors.
#VS and MP-M contributed equally as co-senior authors.
ABSTRACT
Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors are consid- ered a breakthrough in cancer therapy. Currently approved for breast cancer treatment, CDK4/6 inhibitors are extensively test- ed 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 dor- mant 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 differ- entiated 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.
Introduction
Cyclin-dependent kinases (CDK) 4 and 6 are best known for their roles in the mammalian cell cycle. Both are ubiquitously expressed, share 71% sequence homology and form complexes by binding to D-type cyclins (D1, D2 and D3).1 Cyclin D-CDK complexes phosphorylate the gatekeeper retinoblastoma (RB) and the related pocket proteins p107 and p130. In the hyper-phosphorylated state, RB proteins dissociate from E2F transcription factors which subsequently are freed to initiate gene transcription allowing the transition of the cell cycle from G1 to S phase.2,3 The CDK4/6-cyclin D-RB-E2F pathway is one of the most frequently dysregulated pathways in cancer; about 40% of human tumors display alterations in these proteins.3,4
In murine models, the combined loss of CDK4 and CDK6 is lethal in late embryonic or early postnatal development, which was considered to be a conse- quence of severe anemia.5 CDK4 or CDK6 deficiency alone is mostly tolerated in the hematopoietic system implying many overlapping or compensatory functions of both proteins: CDK6 knockout mice are viable, fertile and show hematopoietic
Hematopoiesis
Correspondence:
VERONIKA SEXL
veronika.sexl@vetmeduni.ac.at
Received: April 22, 2020. Accepted: August 21, 2020. Pre-published: August 27,2020.
https://doi.org/10.3324/haematol.2020.256313 ©2021 Ferrata Storti Foundation
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