CDK6 as a key regulator of hematopoietic and leukemic stem cell activation

Blood
Ruth ScheicherVeronika Sexl

Abstract

The cyclin-dependent kinase 6 (CDK6) and CDK4 have redundant functions in regulating 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, Cdk6(-/-) HSCs do not efficiently repopulate upon competitive transplantation, and Cdk6-deficient mice are significantly more susceptible to 5-fluorouracil treatment. We find that activation of HSCs requires CDK6, which interferes with the transcription of key regulators, including Egr1. Transcriptional profiling of HSCs is consistent with the central role of Egr1. The impaired repopulation capacity extends to BCR-ABL(p210+) LSCs. Transplantation with BCR-ABL(p210+)-infected bone marrow from Cdk6(-/-) mice fails to induce disease, although recipient mice do harbor LSCs. Egr1 knock-down in Cdk6(-/-) BCR-ABL(p210+) 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 suppresse...Continue Reading

References

Apr 5, 2016·Seminars in Oncology·James S BlachlyMichael Grever
Jan 23, 2016·Stem Cells International·Christian Kosan, Maren Godmann
Mar 28, 2016·Cancer Treatment Reviews·Erika Hamilton, Jeffrey R Infante
Apr 2, 2016·Nature Reviews. Molecular Cell Biology·Per HydbringPiotr Sicinski
May 1, 2015·Stem Cells and Development·Ying LiuJohnny J He
May 20, 2016·Intractable & Rare Diseases Research·Jing TianGuosheng Jiang
Jul 15, 2015·Oncogene·S EmmrichJ H Klusmann
Apr 14, 2016·Current Opinion in Hematology·Ying Liu, Johnny J He
Sep 9, 2016·Expert Opinion on Investigational Drugs·Carmen Di GiovanniGiovanni Marzaro
Jul 15, 2017·British Journal of Haematology·Leo EdlingerAndrea Hoelbl-Kovacic
Jan 3, 2015·Blood·Monica L Guzman
Mar 5, 2019·Molecular Genetics & Genomic Medicine·Kailibinuer AierkenGuzhalinuer Abulizi
Nov 6, 2018·Endocrine-related Cancer·Neil PortmanC Elizabeth Caldon
Mar 13, 2019·Oncotarget·Karoline KollmannChristoph Hoeller
Jun 21, 2016·Oncotarget·Sophie LopezPaulo De Sepulveda
May 15, 2020·International Journal of Cancer. Journal International Du Cancer·Sofie NebenfuehrVeronika Sexl
Aug 13, 2020·Future Oncology·Miguel MartinEva Ciruelos
Jul 24, 2020·The Journal of Clinical Investigation·Anne MüllerDaniela Kramer
Oct 20, 2019·Nature Communications·Ingeborg MenzlVeronika Sexl
Apr 9, 2020·International Journal of Molecular Sciences·Iris Z UrasKaroline Kollmann
Mar 31, 2019·Nature Communications·Paul KrimpenfortAnton Berns
May 8, 2018·Cellular and Molecular Life Sciences : CMLS·Nicolas CaronBrigitte Malgrange
Sep 16, 2018·Nature Communications·Xufeng ChenXiaolong Liu
May 18, 2020·Nature Reviews. Cancer·Masayuki YamashitaEmmanuelle Passegué
Jun 25, 2020·Breast Cancer Research and Treatment·Ahrong HamJoohyuk Sohn
Dec 14, 2018·International Journal of Molecular Sciences·Iris Z UrasVeronika Sexl
Mar 28, 2018·The Journal of Clinical Investigation·Yaping ZhangJunke Zheng
Jan 16, 2019·Journal of Hematology & Oncology·Alva Rani JamesClaudia D Baldus

Citations

Apr 1, 1996·Hematology/oncology Clinics of North America·M J Thirman, R A Larson
Jul 3, 1997·International Journal of Cancer. Journal International Du Cancer·R P HuangE D Adamson
Oct 18, 2002·Journal of Cellular Physiology·Gerald Thiel, Giuseppe Cibelli
Dec 3, 2002·Nature Reviews. Cancer·Marie Classon, Ed Harlow
Dec 19, 2003·Nucleic Acids Research·Albin SandelinBoris Lenhard
Nov 17, 2004·Genes & Development·Charles J Sherr, James M Roberts
Mar 2, 2005·Cell Cycle·Katarzyna Kozar, Piotr Sicinski
Apr 21, 2005·Blood·Marianna ShafarenkoBarbara Hoffman
Aug 9, 2005·Trends in Cell Biology·Jean C Y Wang, John E Dick
Oct 25, 2007·Nature Reviews. Cancer·Julio A Aguirre-Ghiso
Feb 26, 2008·Cell·Stuart H Orkin, Leonard I Zon
Mar 21, 2008·The Journal of Immunology : Official Journal of the American Association of Immunologists·Motoshi IchikawaMineo Kurokawa
Feb 13, 2009·Nature·Marieke Alida Gertruda EssersAndreas Trumpp
Jul 22, 2009·Bioinformatics·Marc StreitDieter Schmalstieg
Oct 9, 2009·Current Opinion in Genetics & Development·Anne WilsonAndreas Trumpp
Feb 26, 2010·Nature Reviews. Immunology·Andreas TrumppAnne Wilson
Jul 6, 2010·Molecular Oncology·Marieke Alida Gertruda Essers, Andreas Trumpp
Nov 16, 2010·Nature Cell Biology·Olga SirinMargaret A Goodell
Dec 29, 2010·Proceedings of the National Academy of Sciences of the United States of America·David N BooneStephen R Hann
Mar 5, 2011·Current Hematologic Malignancy Reports·Francesca PellicanoTessa L Holyoake
Apr 22, 2011·Blood·Miaofen G HuPhilip W Hinds
Feb 11, 2012·EMBO Molecular Medicine·Boris KovacicHartmut Beug
Aug 3, 2012·Journal of Cell Science·Jun-Kai LaiChia-Che Chang
Aug 21, 2013·Cancer Cell·Karoline KollmannVeronika Sexl
Apr 17, 2014·Cell Cycle·Marieke H van der LindenRonald W Stam
Apr 26, 2014·Blood·Theresa PlackeStefan Fröhling

Related Concepts

EGR1 gene
Colony-Forming Units, Hematopoietic
Fluorouracil
Hematologic Neoplasms
Cyclin-Dependent Kinase 4
Transcription, Genetic
Bone Marrow
Oncogene Protein p185(bcr-abl)
Hematopoiesis, Medullary
CDK4 protein, human

Related Feeds

Blood And Marrow Transplantation

The use of hematopoietic stem cell transplantation or blood and marrow transplantation (bmt) is on the increase worldwide. BMT is used to replace damaged or destroyed bone marrow with healthy bone marrow stem cells. Here is the latest research on bone and marrow transplantation.