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 E. Broxmeyer

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

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

Bibliographical note

Funding Information:
These studies were supported by US Public Health Service grants from the NIH to HEB: R01 DK 109188, U54 DK 106846, R01 HL 056416, R01 HL 112669, and R35 HL 139599. Additional grant support to HEB was provided by the Indiana Clinical and Translational Sciences Institute (CTSI) core pilot grant program. Grant support to MLC was provided by Indiana University Simon Cancer Center American Cancer Society Institutional Research Pilot Grant IRG-16-192-31. MLC was also supported by NIH training grant DK 007519 to HEB for some of these studies. AKS was funded by the Cancer Biology Program of the University of Michigan and grant F30-CA-210379 from the NIH. DMM, NMV, CL, and MS were supported by R01 DK 109188 from the NIH, and DMM and NMV were additionally funded by a grant from the Rheuma- tology Research Foundation. Grant support for HG and FK was provided by the China Scholarship Council, Deutsche Forschungs-gemeinschaft (DFG KA 2799/1), and the START Program of the Faculty of Medicine, RWTH Aachen University.

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