Majumder, Muntasir M and Leppa, Aino-Maija and Hellesoy, Monica and Dowling, Paul and Malyutina, Alina and Kopperud, Reidun and Bazou, Despina and Andersson, Emma and Parsons, Alun and Tang, Jing and Kallioniemi, Olli and Mustjoki, Satu and O'Gorman, Peter and Wennerberg, Krister and Porkka, Kimmo and Gjertsen, Bjorn T and Heckman, Caroline A (2020) Multi-parametric single cell evaluation defines distinct drug responses in healthy hematological cells that are retained in corresponding malignant cell types. Haematologica, 105 (6). pp. 1527-1538. ISSN 0390-6078

Preview

Download (4MB) | Preview

Abstract

Innate drug sensitivity in healthy cells aids identification of lineage specific anti-cancer therapies and reveals off-target effects. To characterize the diversity in drug responses in the major hematopoietic cell types, we simultaneously assessed their sensitivity to 71 small molecules utilizing a multi-parametric flow cytometry assay and mapped their proteomic and basal signaling profiles. Unsupervised hierarchical clustering identified distinct drug responses in healthy cell subsets based on their cellular lineage. Compared to other cell types, CD19+ /B and CD56+ /NK cells were more sensitive to dexamethasone, venetoclax and midostaurin, while monocytes were more sensitive to trametinib. Venetoclax exhibited dose-dependent cell selectivity that inversely correlated to STAT3 phosphorylation. Lineage specific effect of midostaurin was similarly detected in CD19+ /B cells from healthy, acute myeloid leukemia and chronic lymphocytic leukemia samples. Comparison of drug responses in healthy and neoplastic cells showed that healthy cell responses are predictive of the corresponding malignant cell response. Taken together, understanding drug sensitivity in the healthy cell-of-origin provides opportunities to obtain a new level of therapy precision and avoid off-target toxicity.

Item Type:	Article
Additional Information:	©2020 Ferrata Storti Foundation Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher. Cite as: 1. Muntasir M. Majumder, Aino-Maija Leppä, Monica Hellesøy, Paul Dowling, Alina Malyutina, Reidun Kopperud, Despina Bazou, Emma Andersson, Alun Parsons, Jing Tang, Olli Kallioniemi, Satu Mustjoki, Peter O’Gorman, Krister Wennerberg, Kimmo Porkka, Bjørn T. Gjertsen, Caroline A. Heckman. Multi-parametric single cell evaluation defines distinct drug responses in healthy hematologic cells that are retained in corresponding malignant cell types. Haematologica 2020;105(6):1527-1538; https://doi.org/10.3324/haematol.2019.217414.
Keywords:	Multi-parametric; single cell; evaluation; defines; distinct drug responses; healthy hematologic cells; malignant cell types;
Academic Unit:	Faculty of Science and Engineering > Biology
Item ID:	13578
Identification Number:	https://doi.org/10.3324/haematol.2019.217414
Depositing User:	Paul Dowling
Date Deposited:	18 Nov 2020 16:24
Journal or Publication Title:	Haematologica
Publisher:	Ferrata Storti Foundation
Refereed:	Yes
URI:	Publisher
Use Licence:	This item is available under a Creative Commons Attribution Non Commercial Share Alike Licence (CC BY-NC-SA). Details of this licence are available here

Repository Staff Only(login required)

Item control page

Downloads

Origin of downloads