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

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 kinas
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.
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Metadaten
Author: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 Sandra Krause
URN:urn:nbn:de:hebis:30:3-565514
DOI:http://dx.doi.org/10.1038/s41375-020-0866-1
ISSN:1476-5551
Pubmed Id:http://www.ncbi.nlm.nih.gov/pubmed?term=32439895
Parent Title (German):Leukemia
Publisher:Springer Nature
Place of publication:London
Document Type:Article
Language:English
Date of Publication (online):2020/05/21
Date of first Publication:2020/05/21
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/11/04
Volume:34
First Page:2087
Last Page:2101
HeBIS PPN:476221390
Institutes:Biochemie und Chemie
Medizin
Dewey Decimal Classification:610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0

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