Secreted nuclear protein DEK regulates hematopoiesis through CXCR2 signaling

Maegan L. Capitano, Nirit Mor-Vaknin, Anjan K. Saha, Scott Cooper, Maureen Legendre, Haihong Guo, Rafael Contreras-Galindo, Ferdinand Kappes, Maureen A. Sartor, Christopher T. Lee, Xinxin Huang, David M. Markovitz, Hal Broxmeyer

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

The nuclear protein DEK is an endogenous DNA-binding chromatin factor regulating hematopoiesis. DEK is one of only 2 known secreted nuclear chromatin factors, but whether and how extracellular DEK regulates hematopoiesis is not known. We demonstrated that extracellular DEK greatly enhanced ex vivo expansion of cytokine-stimulated human and mouse hematopoietic stem cells (HSCs) and regulated HSC and hematopoietic progenitor cell (HPC) numbers in vivo and in vitro as determined both phenotypically (by flow cytometry) and functionally (through transplantation and colony formation assays). Recombinant DEK increased long-term HSC numbers and decreased HPC numbers through a mechanism mediated by the CXC chemokine receptor CXCR2 and heparan sulfate proteoglycans (HSPGs) (as determined utilizing Cxcr2–/– mice, blocking CXCR2 antibodies, and 3 different HSPG inhibitors) that was associated with enhanced phosphorylation of ERK1/2, AKT, and p38 MAPK. To determine whether extracellular DEK required nuclear function to regulate hematopoiesis, we utilized 2 mutant forms of DEK: one that lacked its nuclear translocation signal and one that lacked DNA-binding ability. Both altered HSC and HPC numbers in vivo or in vitro, suggesting the nuclear function of DEK is not required. Thus, DEK acts as a hematopoietic cytokine, with the potential for clinical applicability.

Original languageEnglish (US)
Pages (from-to)2555-2570
Number of pages16
JournalJournal of Clinical Investigation
Volume129
Issue number6
DOIs
StatePublished - Jun 3 2019

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Hematopoiesis
Nuclear Proteins
Hematopoietic Stem Cells
Cell Count
Heparan Sulfate Proteoglycans
Chromatin
CXCR Receptors
Cytokines
Blocking Antibodies
DNA
p38 Mitogen-Activated Protein Kinases
Flow Cytometry
Transplantation
Phosphorylation

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Capitano, M. L., Mor-Vaknin, N., Saha, A. K., Cooper, S., Legendre, M., Guo, H., ... Broxmeyer, H. (2019). Secreted nuclear protein DEK regulates hematopoiesis through CXCR2 signaling. Journal of Clinical Investigation, 129(6), 2555-2570. https://doi.org/10.1172/JCI127460

Secreted nuclear protein DEK regulates hematopoiesis through CXCR2 signaling. / Capitano, Maegan L.; Mor-Vaknin, Nirit; Saha, Anjan K.; Cooper, Scott; Legendre, Maureen; Guo, Haihong; Contreras-Galindo, Rafael; Kappes, Ferdinand; Sartor, Maureen A.; Lee, Christopher T.; Huang, Xinxin; Markovitz, David M.; Broxmeyer, Hal.

In: Journal of Clinical Investigation, Vol. 129, No. 6, 03.06.2019, p. 2555-2570.

Research output: Contribution to journalArticle

Capitano, ML, Mor-Vaknin, N, Saha, AK, Cooper, S, Legendre, M, Guo, H, Contreras-Galindo, R, Kappes, F, Sartor, MA, Lee, CT, Huang, X, Markovitz, DM & Broxmeyer, H 2019, 'Secreted nuclear protein DEK regulates hematopoiesis through CXCR2 signaling', Journal of Clinical Investigation, vol. 129, no. 6, pp. 2555-2570. https://doi.org/10.1172/JCI127460
Capitano ML, Mor-Vaknin N, Saha AK, Cooper S, Legendre M, Guo H et al. Secreted nuclear protein DEK regulates hematopoiesis through CXCR2 signaling. Journal of Clinical Investigation. 2019 Jun 3;129(6):2555-2570. https://doi.org/10.1172/JCI127460
Capitano, Maegan L. ; Mor-Vaknin, Nirit ; Saha, Anjan K. ; Cooper, Scott ; Legendre, Maureen ; Guo, Haihong ; Contreras-Galindo, Rafael ; Kappes, Ferdinand ; Sartor, Maureen A. ; Lee, Christopher T. ; Huang, Xinxin ; Markovitz, David M. ; Broxmeyer, Hal. / Secreted nuclear protein DEK regulates hematopoiesis through CXCR2 signaling. In: Journal of Clinical Investigation. 2019 ; Vol. 129, No. 6. pp. 2555-2570.
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