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J Immunol. 2016 May 15;196(10):4110-21. doi: 10.4049/jimmunol.1501037. Epub 2016 Apr 18.

Dok1 and Dok2 Proteins Regulate Cell Cycle in Hematopoietic Stem and Progenitor Cells.

Author information

1
INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, 13009 Marseille, France; Institut Paoli-Calmettes, 13009 Marseille, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7258, Centre de Recherche en Cancérologie de Marseille, 13009 Marseille, France; Université d'Aix-Marseille, UM105, 13009 Marseille, France; coppine@pitt.edu jacques.nunes@inserm.fr.
2
INSERM, U1068, Centre de Recherche en Cancérologie de Marseille, 13009 Marseille, France; Institut Paoli-Calmettes, 13009 Marseille, France; Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7258, Centre de Recherche en Cancérologie de Marseille, 13009 Marseille, France; Université d'Aix-Marseille, UM105, 13009 Marseille, France;
3
Cancer Genetics Program, Beth Israel Deaconess Cancer Center, Harvard Medical School, Boston, MA 02215; Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; and Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215.

Abstract

Dok1 and Dok2 proteins play a crucial role in myeloid cell proliferation as demonstrated by Dok1 and Dok2 gene inactivation, which induces a myeloproliferative disease in aging mice. In this study, we show that Dok1/Dok2 deficiency affects myeloproliferation even at a young age. An increase in the cellularity of multipotent progenitors is observed in young Dok1/Dok2-deficient mice. This is associated with an increase in the cells undergoing cell cycle, which is restricted to myeloid committed progenitors. Furthermore, cellular stress triggered by 5-fluorouracil (5-FU) treatment potentiates the effects of the loss of Dok proteins on multipotent progenitor cell cycle. In addition, Dok1/Dok2 deficiency induces resistance to 5-FU-induced hematopoietic stem cell exhaustion. Taken together, these results demonstrate that Dok1 and Dok2 proteins are involved in the control of hematopoietic stem cell cycle regulation.

PMID:
27183638
DOI:
10.4049/jimmunol.1501037
[Indexed for MEDLINE]
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