%0 Journal Article
%A Scheicher, Ruth
%A Hoelbl-Kovacic, Andrea
%A Bellutti, Florian
%A Tigan, Anca-Sarmiza
%A Prchal-Murphy, Michaela
%A Heller, Gerwin
%A Schneckenleithner, Christine
%A Salazar Roa, María
%A Zochbauer-Muller, Sabine
%A Zuber, Johannes
%A Malumbres, Marcos
%A Kollmann, Karoline
%A Sexl, Veronika
%T CDK6 as a key regulator of hematopoietic and leukemic stem cell activation
%D 2015
%@ 0006-4971
%U https://hdl.handle.net/20.500.14352/97337
%X The cyclin-dependent kinase 6 (CDK6) and CDK4 have redundant functions in reg- ulating cell-cycle progression. We describe a novel role for CDK6 in hematopoietic and leukemic stem cells (hematopoietic stem cells [HSCs] and leukemic stem cells [LSCs]) that exceeds its function as a cell-cycle regulator. Although hematopoiesis appears normal under steady-state conditions, Cdk62/2 HSCs do not efficiently repopulate upon competitive transplantation, and Cdk6-deficient mice are significantly more sus- ceptible to 5-fluorouracil treatment. We find that activation of HSCs requires CDK6, which interferes with the transcription of key regulators, including Egr1. Transcrip- tional profiling of HSCs is consistent with the central role of Egr1. The impaired repopulation capacity extends to BCR-ABLp2101 LSCs. Transplantation with BCR- ABLp2101–infected bone marrow from Cdk62/2 mice fails to induce disease, although recipient mice do harbor LSCs. Egr1 knock-down in Cdk62/2 BCR-ABLp2101 LSKs significantly enhances the potential to form colonies, underlining the importance of the CDK6-Egr1 axis. Our findings define CDK6 as an important regulator of stem cell activation and an essential component of a transcriptional complex that suppresses Egr1 in HSCs and LSCs.
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