TNF-α-induced alterations in stromal progenitors enhance leukemic stem cell growth via CXCR2 signaling

Cell Rep. 2021 Jul 13;36(2):109386. doi: 10.1016/j.celrep.2021.109386.

Abstract

Chronic myeloid leukemia (CML) is propagated by leukemia stem cells (LSCs) that are not eradicated by tyrosine kinase inhibitor (TKI) treatment and persist as a source of disease recurrence. Bone marrow (BM) mesenchymal niches play an essential role in hematopoietic stem cell (HSC) and LSC maintenance. Using a murine CML model, we examine leukemia-induced alterations in mesenchymal cell populations. We show that 6C3+ stromal progenitors expand in CML BM and exhibit increased LSC but reduced HSC supportive capacity. Tumor necrosis factor alpha (TNF-α) signaling mediates expansion and higher expression of CXCL1 in CML BM 6C3+ cells and higher expression of the CXCL1 receptor CXCR2 in LSCs. CXCL1 enhances LSC proliferation and self-renewal, whereas CXCR2 inhibition reduces LSC growth and enhances LSC targeting in combination with tyrosine kinase inhibitors (TKIs). We find that TNF-α-mediated alterations in CML BM stromal niches enhance support of LSC maintenance and growth via CXCL1-CXCR2 signaling and that CXCR2 inhibition effectively depletes CML LSCs.

Keywords: 6C3; CML; CXCL1; CXCR2; TNF-α; bone marrow microenvironment; inflammation; leukemic stem cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Animals
  • Bone Marrow / pathology
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • Chemokines / metabolism
  • Gene Expression Regulation, Leukemic / drug effects
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Inflammation / genetics
  • Inflammation / pathology
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / genetics
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / metabolism*
  • Leukemia, Myelogenous, Chronic, BCR-ABL Positive / pathology*
  • Mesenchymal Stem Cells / drug effects
  • Mesenchymal Stem Cells / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Middle Aged
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Receptors, Interleukin-8B / metabolism*
  • Signal Transduction* / drug effects
  • Tumor Necrosis Factor-alpha / metabolism*

Substances

  • Chemokines
  • Protein Kinase Inhibitors
  • Receptors, Interleukin-8B
  • Tumor Necrosis Factor-alpha