TY  - JOUR
A1  - Kumar, Rahul
A1  - Pereira, Raquel Soares
A1  - Zanetti, Costanza
A1  - Minciacchi, Valentina R.
A1  - Merten, Maximilian
A1  - Meister, Melanie
A1  - Niemann, Julian
A1  - Dietz, Marina
A1  - Rüssel, Nina
A1  - Schnütgen, Frank
A1  - Tamai, Minori
A1  - Akahane, Koshi
A1  - Inukai, Takeshi
A1  - Oellerich, Thomas
A1  - Kvasnicka, Hans Michael
A1  - Pfeifer, Heike
A1  - Nicolini, Franck E.
A1  - Heilemann, Mike
A1  - Van Etten, Richard A.
A1  - Krause, Daniela Sandra
T1  - Specific, targetable interactions with the microenvironment influence imatinib-resistant chronic myeloid leukemia
T2  - Leukemia
N2  - 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.
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/56551
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-565514
SN  - 1476-5551
VL  - 34
SP  - 2087
EP  - 2101
PB  - Springer Nature
CY  - London
ER  -