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  The vascular bone marrow niche influences outcome in chronic myeloid leukemia via the E-selectin - SCL/TAL1-CD44 axis.

Godavarthy, P. S., Kumar, R., Herkt, S. C., Pereira, R. S., Hayduk, N., Weissenberger, E. S., et al. (2020). The vascular bone marrow niche influences outcome in chronic myeloid leukemia via the E-selectin - SCL/TAL1-CD44 axis. Haematologica, 105(1), 136-147. doi:10.3324/haematol.2018.212365.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0005-7955-4 Version Permalink: http://hdl.handle.net/21.11116/0000-0005-795B-E
Genre: Journal Article

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 Creators:
Godavarthy, P. S., Author
Kumar, R., Author
Herkt, S. C., Author
Pereira, R. S., Author
Hayduk, N., Author
Weissenberger, E. S., Author
Aggoune, D., Author
Manavski, Y., Author
Lucas, T., Author
Pan, K. T.1, Author              
Voutsinas, J. M., Author
Wu, Q., Author
Müller, M. C., Author
Saussele, S., Author
Oellerich, T., Author
Oehler, V. G., Author
Lausen, J., Author
Krause, D. S., Author
Affiliations:
1Research Group of Bioanalytical Mass Spectrometry, MPI for Biophysical Chemistry, Max Planck Society, ou_578613              

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 Abstract: The endosteal bone marrow niche and vascular endothelial cells provide sanctuaries for leukemic cells. In murine chronic myeloid leukemia (CML) CD44 on leukemia cells and E-selectin on bone marrow endothelium are essential mediators for the engraftment of leukemic stem cells. We hypothesized that non-adhesion of CML-initiating cells to E-selectin on the bone marrow endothelium may lead to superior eradication of leukemic stem cells in CML after treatment with imatinib than imatinib alone. Indeed, here we show that treatment with the E-selectin inhibitor GMI-1271 in combination with imatinib prolongs survival of mice with CML via decreased contact time of leukemia cells with bone marrow endothelium. Non-adhesion of BCR-ABL1(+) cells leads to an increase of cell cycle progression and an increase of expression of the hematopoietic transcription factor and proto-oncogene Scl/Tal1 in leukemia-initiating cells. We implicate SCL/TAL1 as an indirect phosphorylation target of BCR-ABL1 and as a negative transcriptional regulator of CD44 expression. We show that increased SCL/TAL1 expression is associated with improved outcome in human CML. These data demonstrate the BCR-ABL1-specific, cell-intrinsic pathways leading to altered interactions with the vascular niche via the modulation of adhesion molecules - which could be exploited therapeutically in the future.

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Language(s): eng - English
 Dates: 2020-01
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.3324/haematol.2018.212365
 Degree: -

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Title: Haematologica
Source Genre: Journal
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Pages: - Volume / Issue: 105 (1) Sequence Number: - Start / End Page: 136 - 147 Identifier: -