Open AccessReversible switching of leukemic cells to a drug-resistant, stem-like subset via IL-4-mediated cross-talk with mesenchymal stroma
Author(s) -
Haeri Lee,
GaYoung Lee,
Eung-Won Kim,
Hee-Je Kim,
Minho Lee,
R. Keith Humphries,
IlHoan Oh
Publication year - 2021
Publication title -
haematologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.782
H-Index - 142
eISSN - 1592-8721
pISSN - 0390-6078
DOI - 10.3324/haematol.2020.269944
Subject(s) - mesenchymal stem cell , stroma , stromal cell , cancer research , biology , microbiology and biotechnology , progenitor cell , cell , stem cell , immunology , genetics , immunohistochemistry
Chemoresistance of leukemic cells has largely been attributed to clonal evolution secondary to accumulating mutations. Here, we show that a subset of leukemic blasts in contact with the mesenchymal stroma undergo cellular conversion into a distinct cell type that exhibits a stem cell-like phenotype and chemoresistance. These stroma-induced changes occur in a reversible and stochastic manner driven by cross-talk, whereby stromal contact induces interleukin-4 in leukemic cells that in turn targets the mesenchymal stroma to facilitate the development of new subset. This mechanism was dependent on interleukin-4-mediated upregulation of vascular cell adhesion molecule- 1 in mesenchymal stroma, causing tight adherence of leukemic cells to mesenchymal progenitors for generation of new subsets. Together, our study reveals another class of chemoresistance in leukemic blasts via functional evolution through stromal cross-talk, and demonstrates dynamic switching of leukemic cell fates that could cause a non-homologous response to chemotherapy in concert with the patient-specific microenvironment.