RT Journal Article
T1 CDK6 as a key regulator of hematopoietic and leukemic stem cell activation
A1 Scheicher, Ruth
A1 Hoelbl-Kovacic, Andrea
A1 Bellutti, Florian
A1 Tigan, Anca-Sarmiza
A1 Prchal-Murphy, Michaela
A1 Heller, Gerwin
A1 Schneckenleithner, Christine
A1 Salazar Roa, María
A1 Zochbauer-Muller, Sabine
A1 Zuber, Johannes
A1 Malumbres, Marcos
A1 Kollmann, Karoline
A1 Sexl, Veronika
AB 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.
PB The American Society of Hematology
SN 0006-4971
YR 2015
FD 2015
LK https://hdl.handle.net/20.500.14352/97337
UL https://hdl.handle.net/20.500.14352/97337
LA eng
NO Ruth Scheicher, Andrea Hoelbl-Kovacic, Florian Bellutti, Anca-Sarmiza Tigan, Michaela Prchal-Murphy, Gerwin Heller, Christine Schneckenleithner, María Salazar-Roa, Sabine Zöchbauer-Müller, Johannes Zuber, Marcos Malumbres, Karoline Kollmann, Veronika Sexl; CDK6 as a key regulator of hematopoietic and leukemic stem cell activation. Blood 2015; 125 (1): 90–101. doi: https://doi.org/10.1182/blood-2014-06-584417
NO Austrian Science Foundation
DS Docta Complutense
RD 18 abr 2025