UNCOUPLING INK PROTEINS FROM CDK4/CDK6 IN HSCS - UNCOUPLING PROLIFERATION FROM SENESCENCE
Author(s): ,
Michaela Prchal-Murphy
Affiliations:
Department for Biomedical Science,Institute of Pharmacology and Toxicology, VetMed University Vienna,Vienna,Austria
,
Florian Bellutti
Affiliations:
Department for Biomedical Science,Institute of Pharmacology and Toxicology, VetMed University Vienna,Vienna,Austria
,
Veronika Sexl
Affiliations:
Department for Biomedical Science,Institute of Pharmacology and Toxicology, VetMed University Vienna,Vienna,Austria
Karoline Kollmann
Affiliations:
Department for Biomedical Science,Institute of Pharmacology and Toxicology, VetMed University Vienna,Vienna,Austria
EHA Library. Prchal-Murphy M. Jun 15, 2019; 267184; PS1567
Dr. Michaela Prchal-Murphy
Dr. Michaela Prchal-Murphy
Contributions
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Abstract

Abstract: PS1567

Type: Poster Presentation

Presentation during EHA24: On Saturday, June 15, 2019 from 17:30 - 19:00

Location: Poster area

Background
Cyclin-dependent kinase (CDK) 4 and CDK6 are highly related cell-cycle kinases that regulate progression from G1 to S-phase. CDK4/6 are activated upon binding of D-type cyclins and subsequently phosphorylate the retinoblastoma protein (Rb). CDK4/6 inhibitor proteins, the INK4 family (p16INK4a, p15INK4b, p18INK4c, and p19INK4d) as major player, adds another layer of complexity. Hyperactivity of CDK4 or CDK6 is frequently observed in hematopoietic malignancies due to loss of p16INK4a. Besides, CDK6 has also been identified as transcriptional regulator driving complex transcriptional programs. CDK4/6 inhibitors are approved in breast cancer treatment and are currently tested in hematopoietic malignancies.

Aims
We aimed to unravel the consequences of the loss of these inhibitory INK-dependent mechanisms for hematopoiesis.

Methods
We used knock-in mice expressing a CDK6 (CDK6R31C, Cdk6R/R) and/or a CDK4 (CDK4R24C, Cdk4R/R) mutant insensitive to INK4-mediated inhibition and analyzed stem cell populations. Further we tested the self-renewal capacity of mutant hematopoietic progenitors under conditions of hematopoietic stress.

Results
Despite comparable bone marrow cellularity, we found a significant reduction in LSK cells and HSC populations in mice harboring Cdk4R/R or Cdk6R/R mutation. The combination of Cdk4R/R/Cdk6R/R in double-knock-in mice rescued these defects in all progenitor stages. Serially transplanted Cdk4R/R/Cdk6R/R double-knock-in HSCs display enhanced stem cell proliferation. They maintain the ability to give rise to both myeloid and lymphoid lineages. In response to hematopoietic stress (5-FU, serial and competitive total bone marrow transplantation), CDK4R24C/CDK6R31C prevents stem cell exhaustion and show robust recovery in stem cell numbers. Low-input RNAseq of long-term stress-triggered HSCs will unravel mechanisms uncoupling proliferation from senescence.

Conclusion
HSCs with disrupted CDK4/6 – INK4 binding show enhanced proliferation, reduced exhaustion and improved transplant ability. Analysis of the underlying molecular alterations may open novel therapeutic options for CDK4/6 hyperactive hematopoietic malignancies. 

Session topic: 21. Stem cell transplantation - Experimental

Keyword(s): Cell cycle progression, Hematopoietic stem and progenitor cells, Stem cell transplant

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