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

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.

Mast Cells Are Crucial for Induction of Group 2 Innate Lymphoid Cells and Clearance of Helminth Infections

“…The number of total mononuclear cells, Lin À Sca1 + c-Kit + cells, and Lin À Sca1 À c-Kit + myeloid progenitors (MPs) in the bone marrow of Spib À/À mice was comparable to WT mice ( Figures 3B and 3C). MPs are further divided into CMP, GMP, and MEP based on the expression of CD34 and FcgRII/III (Coppin et al, 2016). While these three progenitors were numerically similar in WT bone marrow, there were more GMP and fewer MEP in the Spib À/À mice ( Figures 3C and 3D).…”

Methylation‐associated DOK1 and DOK2 down‐regulation: Potential biomarkers for predicting adverse prognosis in acute myeloid leukemia

“…Tumor suppressing roles of DOK1 / 2 have been reported in solid tissues and hematopoietic compartment in several studies (Berger et al, ; Coppin et al, ; Ghanem, Bracken, Kasem, Jiang, & Mokbel, ; Lee et al, , 2007; Niki et al, ; Yasuda et al, ). Genetic disruption of DOK1 / 2 in animal models and human tumor samples increased their susceptibility to leukemia development (Celis‐Gutierrez et al, ; Coppin et al, ; Mashima et al, , ; Niki et al, ; Yasuda et al, ). Niki et al () and Yasuda et al () through functional studies in vivo revealed that DOK1 / 2 inactivation resulted in hyperplasia of myeloid progenitors at various stages and markedly accelerated leukemia.…”

“…Downstream of tyrosine kinase ( DOK ), a large family of phosphotyrosine adapters, are substrates of protein tyrosine kinases (Coppin et al, ). Seven members ( DOK1 – DOK7 ) of DOK family have been identified, and these members were found to be implicated in the regulation of multiple biological processes, including cell growth, transformation, differentiation, motility, and death (Celis‐Gutierrez et al, ; Mashima, Hishida, Tezuka, & Yamanashi, , Mashima et al, ).…”

Dok-1 and Dok-2 Are Required To Maintain Herpes Simplex Virus 1-Specific CD8+T Cells in a Murine Model of Ocular Infection

“…These two closely related Dok family members are involved in the regulation of several cellular processes, such as proliferation, differentiation, and migration. Using Dok-1-and -2 (Dok-1/2)-deficient mice, biological roles for Dok-1 and Dok-2 have been demonstrated in antibody responses to thymus-dependent antigens, NK and hematopoietic cell development and function, innate immune response to lipopolysaccharide (LPS), myeloid homeostasis, and leukemia suppression (29)(30)(31)(32)(33)(34)(35)(36). In addition, we recently demonstrated that Dok proteins regulate the CD8 ϩ T cell response to an exogenous epitope expressed by vaccinia virus (VV) (37).…”