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

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

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

Kuvaus

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.
Alkuperäiskielienglanti
LehtiHaematologica
Sivuthaematol.2019.217414
ISSN0390-6078
DOI - pysyväislinkit
TilaJulkaistu - 22 elokuuta 2019
OKM-julkaisutyyppiA1 Alkuperäisartikkeli tieteellisessä aikakauslehdessä, vertaisarvioitu

Tieteenalat

  • 3111 Biolääketieteet

Lainaa tätä

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title = "Multi-parametric single cell evaluation defines distinct drug responses in healthy hematological cells that are retained in corresponding malignant cell types",
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.",
keywords = "3111 Biomedicine",
author = "Majumder, {Muntasir M.} and Aino-Maija Lepp{\"a} and Monica Helles{\o}y and Paul Dowling and Alina Malyutina and Reidun Kopperud and Despina Bazou and Emma Andersson and Alun Parsons and Jing Tang and Olli Kallioniemi and Satu Mustjoki and Peter O'Gorman and Krister Wennerberg and Kimmo Porkka and Gjertsen, {Bj{\o}rn T.} and Heckman, {Caroline A.}",
year = "2019",
month = "8",
day = "22",
doi = "10.3324/haematol.2019.217414",
language = "English",
pages = "haematol.2019.217414",
journal = "Haematologica",
issn = "0390-6078",
publisher = "FERRATA STORTI FOUNDATION",

}

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

julkaisussa: Haematologica, 22.08.2019, s. haematol.2019.217414.

Tutkimustuotos: ArtikkelijulkaisuArtikkeliTieteellinenvertaisarvioitu

TY - JOUR

T1 - Multi-parametric single cell evaluation defines distinct drug responses in healthy hematological cells that are retained in corresponding malignant cell types

AU - Majumder, Muntasir M.

AU - Leppä, Aino-Maija

AU - Hellesøy, Monica

AU - Dowling, Paul

AU - Malyutina, Alina

AU - Kopperud, Reidun

AU - Bazou, Despina

AU - Andersson, Emma

AU - Parsons, Alun

AU - Tang, Jing

AU - Kallioniemi, Olli

AU - Mustjoki, Satu

AU - O'Gorman, Peter

AU - Wennerberg, Krister

AU - Porkka, Kimmo

AU - Gjertsen, Bjørn T.

AU - Heckman, Caroline A.

PY - 2019/8/22

Y1 - 2019/8/22

N2 - 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.

AB - 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.

KW - 3111 Biomedicine

U2 - 10.3324/haematol.2019.217414

DO - 10.3324/haematol.2019.217414

M3 - Article

SP - haematol.2019.217414

JO - Haematologica

JF - Haematologica

SN - 0390-6078

ER -