C-X-C motif chemokine 12 influences the development of extramedullary hematopoiesis in the spleens of myelofibrosis patients

Exp Hematol. 2015 Feb;43(2):100-9.e1. doi: 10.1016/j.exphem.2014.10.013. Epub 2014 Nov 8.

Abstract

Myelofibrosis (MF) is characterized by the constitutive mobilization of hematopoietic stem cells (HSC) and hematopoietic progenitor cells (HPC) and the establishment of extramedullary hematopoiesis. The mechanisms underlying this abnormal HSC/HPC trafficking pattern remain poorly understood. We demonstrated that both splenic and peripheral blood (PB) MF CD34(+) cells equally share a defective ability to home to the marrow, but not to the spleens, of NOD/LtSz-Prkdc(scid) mice. This trafficking pattern could not be attributed to discordant expression of integrins or chemokine receptors other than the downregulation of C-X-C chemokine receptor type 4 by both PB and splenic MF CD34(+) cells. The number of both splenic MF CD34(+) cells and HPCs that migrated toward splenic MF plasma was, however, significantly greater than the number that migrated toward PB MF plasma. The concentration of the intact HSC/HPC chemoattractant C-X-C motif chemokine 12 (CXCL12) was greater in splenic MF plasma than PB MF plasma, as quantified using mass spectrometry. Functionally inactive truncated products of CXCL12, which are the product of proteolytic degradation by serine proteases, were detected at similar levels in both splenic and PB MF plasma. Treatment with an anti-CXCL12 neutralizing antibody resulted in a reduction in the degree of migration of splenic MF CD34(+) cells toward both PB and splenic MF plasma, validating the role of CXCL12 as a functional chemoattractant. Our data indicate that the MF splenic microenvironment is characterized by increased levels of intact, functional CXCL12, which contributes to the localization of MF CD34(+) cells to the spleen and the establishment of extramedullary hematopoiesis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Aged
  • Animals
  • Antibodies, Neutralizing / pharmacology
  • Antigens, CD34 / genetics
  • Antigens, CD34 / immunology
  • Bone Marrow / immunology*
  • Bone Marrow / pathology
  • Cells, Cultured
  • Cellular Microenvironment
  • Chemokine CXCL12 / antagonists & inhibitors
  • Chemokine CXCL12 / genetics
  • Chemokine CXCL12 / immunology*
  • Chemotaxis
  • Female
  • Gene Expression
  • Hematopoiesis, Extramedullary*
  • Humans
  • Janus Kinase 2 / genetics
  • Janus Kinase 2 / immunology
  • Leukocytes, Mononuclear / immunology*
  • Leukocytes, Mononuclear / pathology
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Middle Aged
  • Mutation
  • Primary Myelofibrosis / genetics
  • Primary Myelofibrosis / immunology*
  • Primary Myelofibrosis / pathology
  • Proteolysis
  • Spleen / immunology*
  • Spleen / pathology
  • Spleen / surgery
  • Splenectomy

Substances

  • Antibodies, Neutralizing
  • Antigens, CD34
  • CXCL12 protein, human
  • Chemokine CXCL12
  • JAK2 protein, human
  • Janus Kinase 2