Specific, targetable interactions with the microenvironment influence imatinib-resistant chronic myeloid leukemia.

Abstract

Therapy resistance in leukemia may be due to cancer cell-intrinsic and/or -extrinsic mechanisms. Mutations within BCR-ABL1, the oncogene giving rise to chronic myeloid leukemia (CML), lead to resistance to tyrosine kinase inhibitors (TKI), and some are associated with clinically more aggressive disease and worse outcome. Using the retroviral transduction/transplantation model of CML and human cell lines we faithfully recapitulate accelerated disease course in TKI resistance. We show in various models, that murine and human imatinib-resistant leukemia cells positive for the oncogene BCR-ABL1T315I differ from BCR-ABL1 native (BCR-ABL1) cells with regards to niche location and specific niche interactions. We implicate a pathway via integrin β3, integrin-linked kinase (ILK) and its role in deposition of the extracellular matrix (ECM) protein fibronectin as causative of these differences. We demonstrate a trend towards a reduced BCR-ABL1T315I+ tumor burden and significantly prolonged survival of mice with BCR-ABL1T315I+ CML treated with fibronectin or an ILK inhibitor in xenogeneic and syngeneic murine transplantation models, respectively. These data suggest that interactions with ECM proteins via the integrin β3/ILK-mediated signaling pathway in BCR-ABL1T315I+ cells differentially and specifically influence leukemia progression. Niche targeting via modulation of the ECM may be a feasible therapeutic approach to consider in this setting.

• Authors: Rahul Kumar, Raquel S Pereira, Costanza Zanetti, Valentina R Minciacchi, Maximilian Merten, Melanie Meister, Julian Niemann, Marina S Dietz, Nina Rüssel, Frank Schnütgen, Minori Tamai, Koshi Akahane, Takeshi Inukai, Thomas Oellerich, Hans Michael Kvasnicka, Heike Pfeifer, Franck E Nicolini, Mike Heilemann, Richard A Van Etten, Daniela S Krause
• Journal: Leukemia (Leukemia) Vol. 34 Issue 8 Pg. 2087-2101 (08 2020) ISSN: 1476-5551 [Electronic] England
• PMID: 32439895 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BCR-ABL1 fusion protein, human
• Fibronectins
• Imidazoles
• Integrin beta3
• Pyridazines
• ponatinib
• Imatinib Mesylate
• integrin-linked kinase
• Focal Adhesion Protein-Tyrosine Kinases
• Fusion Proteins, bcr-abl
• Protein Serine-Threonine Kinases

Topics

• Animals
• Drug Resistance, Neoplasm
• Fibronectins (analysis, metabolism)
• Focal Adhesion Protein-Tyrosine Kinases (physiology)
• Fusion Proteins, bcr-abl (analysis, physiology)
• Humans
• Imatinib Mesylate (therapeutic use)
• Imidazoles (pharmacology)
• Integrin beta3 (physiology)
• Leukemia, Myelogenous, Chronic, BCR-ABL Positive (drug therapy)
• Mice
• Protein Serine-Threonine Kinases (antagonists & inhibitors, physiology)
• Pyridazines (pharmacology)