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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 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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Author:Rahul KumarORCiD, Raquel Soares PereiraGND, Costanza ZanettiORCiDGND, Valentina R. MinciacchiORCiD, Maximilian Merten, Melanie Meister, Julian Niemann, Marina DietzORCiDGND, Nina Rüssel, Frank SchnütgenORCiDGND, Minori Tamai, Koshi Akahane, Takeshi Inukai, Thomas OellerichORCiD, Hans Michael KvasnickaORCiD, Heike Pfeifer, Franck E. Nicolini, Mike HeilemannORCiDGND, Richard A. Van Etten, Daniela Sandra KrauseORCiDGND
URN:urn:nbn:de:hebis:30:3-565514
DOI:https://doi.org/10.1038/s41375-020-0866-1
ISSN:1476-5551
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/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, Chemie und Pharmazie / Biochemie und Chemie
Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Sammlungen:Universitätspublikationen
Licence (German):License LogoCreative Commons - Namensnennung 4.0