Tyrosine kinase inhibitors induce mesenchymal stem cell-mediated resistance in BCR-ABL+ acute lymphoblastic leukemia Academic Article uri icon

Overview

MeSH Major

  • Drug Resistance, Neoplasm
  • Fusion Proteins, bcr-abl
  • Mesenchymal Stromal Cells
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma
  • Protein Kinase Inhibitors

abstract

  • Tyrosine kinase inhibitors (TKIs) are used as a frontline therapy for BCR-ABL(+) acute lymphoblastic leukemia (ALL). However, resistance to TKI therapy arises rapidly, and its underlying molecular mechanisms are poorly understood. In this study, we identified a novel cascade of events initiated by TKIs and traversing through mesenchymal stem cells (MSCs) to leukemic cells, leading to resistance. MSCs exposed to TKIs acquired a new functional status with the expression of genes encoding for chemo-attractants, adhesion molecules, and prosurvival growth factors, and this priming enabled leukemic cells to form clusters underneath the MSCs. This cluster formation was associated with the protection of ALL cells from therapy as leukemic cells switched from BCR-ABL signaling to IL-7R/Janus kinase signaling to survive in the MSC milieu. Our findings illustrate a novel perspective in the evolution of TKI resistance and provide insights for advancing the treatment of BCR-ABL(+) ALL.

publication date

  • January 2015

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4424418

Digital Object Identifier (DOI)

  • 10.1182/blood-2014-05-576421

PubMed ID

  • 25712988

Additional Document Info

start page

  • 2968

end page

  • 73

volume

  • 125

number

  • 19