Multi-parametric single cell evaluation defines distinct drug responses in healthy hematologic cells that are retained in corresponding malignant cell types

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http://hdl.handle.net/10138/316281

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Majumder , M M , Leppä , A-M , Hellesøy , M , Dowling , P , Malyutina , A , Kopperud , R , Bazou , D , Andersson , E , Parsons , A , Tang , J , Kallioniemi , O , Mustjoki , S , O´Gorman , P , Wennerberg , K , Porkka , K , Gjertsen , B T & Heckman , C A 2020 , ' Multi-parametric single cell evaluation defines distinct drug responses in healthy hematologic cells that are retained in corresponding malignant cell types ' , Haematologica , vol. 105 , no. 6 , pp. 1527-1538 . https://doi.org/10.3324/haematol.2019.217414

Title: Multi-parametric single cell evaluation defines distinct drug responses in healthy hematologic cells that are retained in corresponding malignant cell types
Author: Majumder, Muntasir M.; Leppä, Aino-Maija; Hellesøy, Monica; Dowling, Paul; Malyutina, Alina; Kopperud, Reidun; Bazou, Despina; Andersson, Emma; Parsons, Alun; Tang, Jing; Kallioniemi, Olli; Mustjoki, Satu; O´Gorman, Peter; Wennerberg, Krister; Porkka, Kimmo; Gjertsen, Bjørn T.; Heckman, Caroline A.
Contributor: University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, HUSLAB
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Institute for Molecular Medicine Finland
University of Helsinki, Department of Clinical Chemistry and Hematology
University of Helsinki, Krister Wennerberg / Principal Investigator
University of Helsinki, HUS Comprehensive Cancer Center
University of Helsinki, Research Programs Unit
Date: 2020-06
Language: eng
Number of pages: 12
Belongs to series: Haematologica
ISSN: 0390-6078
URI: http://hdl.handle.net/10138/316281
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.
Subject: 3122 Cancers
ACUTE MYELOID-LEUKEMIA
GLUCOCORTICOID-INDUCED APOPTOSIS
CHRONIC LYMPHOCYTIC-LEUKEMIA
MASS CYTOMETRY
MIDOSTAURIN
INHIBITORS
S100A8
1ST-IN-HUMAN
SENSITIVITY
VENETOCLAX
3111 Biomedicine
ACUTE MYELOID-LEUKEMIA
GLUCOCORTICOID-INDUCED APOPTOSIS
CHRONIC LYMPHOCYTIC-LEUKEMIA
MASS CYTOMETRY
MIDOSTAURIN
INHIBITORS
S100A8
1ST-IN-HUMAN
SENSITIVITY
VENETOCLAX
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