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

SUMMARY 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.
Graphical abstract
In brief Chronic myeloid leukemia (CML) leukemia stem cells (LSCs) resist elimination by treatment. Agarwal et al. show that CML 6C3+ bone marrow stromal progenitors support LSC maintenance. TNF-α signaling mediates increased CXCL1 expression in 6C3+ cells, which support LSC proliferation and self-renewal. Targeting the CXCL1 receptor CXCR2 inhibits LSC maintenance.