Page 69 - Haematologica - Vol. 105 n. 6 - June 2020

Hematopoiesis
Multi-parametric single cell evaluation defines distinct drug responses in healthy hematologic cells that are retained in corresponding malignant cell types
Muntasir M. Majumder,1 Aino-Maija Leppä,1 Monica Hellesøy,2 Paul Dowling,3 Alina Malyutina,1 Reidun Kopperud,4 Despina Bazou,5 Emma Andersson,6 Alun Parsons,1 Jing Tang,1 Olli Kallioniemi,1,7 Satu Mustjoki,6,8 Peter O’Gorman,5 Krister Wennerberg,1,9 Kimmo Porkka,8,10 Bjørn T. Gjertsen2,4 and Caroline A. Heckman1
1Institute for Molecular Medicine Finland FIMM, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland; 2Hematology Section, Department of Internal Medicine, Haukeland University Hospital, Bergen, Norway; 3Department of Biology, National University of Ireland, Maynooth, Ireland; 4Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen, Bergen, Norway; 5Department of Hematology, Mater Misericordiae University Hospital, Dublin, Ireland; 6Department of Clinical Chemistry and Hematology, University of Helsinki, Finland; 7Science for Life Laboratory, Department of Oncology and Pathology, Karolinska Institute, Solna, Sweden; 8Hematology Research Unit Helsinki, University of Helsinki, Helsinki, Finland; 9BRIC-Biotech Research and Innovation Centre, University of Copenhagen, Copenhagen, Denmark and 10Department of Hematology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland
ABSTRACT
Innate drug sensitivity in healthy cells aids identification of lineage specific anti-cancer therapies and reveals off-target effects. To charac- terize 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 pro- teomic 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 midostau- rin, 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 sim- ilarly 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-ori- gin provides opportunities to obtain a new level of therapy precision and avoid off-target toxicity.
Introduction
During hematopoiesis, multipotent stem cells and pluripotent precursors undergo a complex differentiation program to generate a diverse set of blood cell types with wide-ranging phenotypes and functions.1 This process is initiated and driven by dis- tinct signaling pathways linked to the different cellular lineages.2 It is likely that malignant hematopoietic cells exploit many of the signaling pathways essential for maintaining survival and specific functions of normal cells. Identification and under- standing of normal hematopoietic cell type specific pathways could, therefore, be leveraged therapeutically as anti-cancer strategies against their malignant counter- parts. For example, targeting B-cell antigen receptor (BCR) signaling with ibrutinib or idelalisib has proven highly effective in treating chronic lymphocytic leukemia (CLL).3,4 Conversely, modulating molecular targets shared between malignant and
Ferrata Storti Foundation
Haematologica 2020 Volume 105(6):1527-1538
Correspondence:
CAROLINE A. HECKMAN
caroline.heckman@helsinki.fi
MUNTASIR MAMUN MAJUMDER
muntasir.mamun@helsinki.fi
Received: January 24, 2019. Accepted: August 22, 2019. Pre-published: August 22, 2019.
doi:10.3324/haematol.2019.217414
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/6/1527
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