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Phenotype-based drug screening reveals association between venetoclax response and differentiation stage in acute myeloid leukemia.

Abstract

Ex vivo drug testing is a promising approach to identify novel treatment strategies for acute myeloid leukemia. However, accurate blast-specific drug responses cannot be measured with homogeneous "add-mix-measure" cell viability assays. In this study, we implemented a flow cytometry-based approach to simultaneously evaluate the ex vivo sensitivity of different cell populations in 34 primary acute myeloid leukemia samples to seven drugs and 27 rational drug combinations. Our data demonstrate that different cell populations present in acute myeloid leukemia samples have distinct sensitivity to targeted therapies. Particularly, blast cells of FAB M0/1 acute myeloid leukemia showed high sensitivity to venetoclax. In contrast, differentiated monocytic cells abundantly present in M4/5 subtypes showed resistance to Bcl-2 inhibition, whereas immature blasts in the same samples were sensitive, highlighting the importance of blast-specific readouts. Accordingly, in the total mononuclear cell fraction the highest BCL2/MCL1 gene expression ratio was observed in M0/1 and the lowest in M4/5 acute myeloid leukemia. Of the seven tested drugs, venetoclax had the highest blast-specific toxicity, and combining venetoclax with either MEK inhibitor trametinib or JAK inhibitor ruxolitinib effectively targeted all venetoclax-resistant blasts. In conclusion, we show that ex vivo efficacy of targeted agents and particularly Bcl-2 inhibitor venetoclax is influenced by the cell type, and accurate blast-specific drug responses can be assessed with a flow cytometry-based approach.

Authors+Show Affiliations

Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki.Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki.Institute of Biomedicine, Schools of Medicine, University of Eastern Finland, Kuopio.Hematology Research Unit, Helsinki University Hospital Comprehensive Cancer Center, Helsinki.Hematology Research Unit, Helsinki University Hospital Comprehensive Cancer Center, Helsinki.Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki.Hematology Research Unit, Helsinki University Hospital Comprehensive Cancer Center, Helsinki.Hematology Research Unit, Helsinki University Hospital Comprehensive Cancer Center, Helsinki.Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki.Department of Hematology and Oncology, University of Tartu, Tartu.Centre for Cancer Biomarkers, Department of Clinical Science, University of Bergen, Bergen.Institute of Biomedicine, Schools of Medicine, University of Eastern Finland, Kuopio.Hematology Research Unit, Helsinki University Hospital Comprehensive Cancer Center, Helsinki.Hematology Research Unit, Helsinki University Hospital Comprehensive Cancer Center, Helsinki.Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki; caroline.heckman@helsinki.fi.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31296572

Citation

Kuusanmäki, Heikki, et al. "Phenotype-based Drug Screening Reveals Association Between Venetoclax Response and Differentiation Stage in Acute Myeloid Leukemia." Haematologica, 2019.
Kuusanmäki H, Leppä AM, Pölönen P, et al. Phenotype-based drug screening reveals association between venetoclax response and differentiation stage in acute myeloid leukemia. Haematologica. 2019.
Kuusanmäki, H., Leppä, A. M., Pölönen, P., Kontro, M., Dufva, O., Deb, D., ... Heckman, C. A. (2019). Phenotype-based drug screening reveals association between venetoclax response and differentiation stage in acute myeloid leukemia. Haematologica, doi:10.3324/haematol.2018.214882.
Kuusanmäki H, et al. Phenotype-based Drug Screening Reveals Association Between Venetoclax Response and Differentiation Stage in Acute Myeloid Leukemia. Haematologica. 2019 Jul 11; PubMed PMID: 31296572.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Phenotype-based drug screening reveals association between venetoclax response and differentiation stage in acute myeloid leukemia. AU - Kuusanmäki,Heikki, AU - Leppä,Aino-Maija, AU - Pölönen,Petri, AU - Kontro,Mika, AU - Dufva,Olli, AU - Deb,Debashish, AU - Yadav,Bhagwan, AU - Brück,Oscar, AU - Kumar,Ashwini, AU - Everaus,Hele, AU - Gjertsen,Bjørn T, AU - Heinäniemi,Merja, AU - Porkka,Kimmo, AU - Mustjoki,Satu, AU - Heckman,Caroline A, Y1 - 2019/07/11/ PY - 2018/12/17/received PY - 2019/07/08/accepted PY - 2019/7/13/entrez KW - Acute Myeloid Leukemia KW - Drug screening KW - Flow cytometry KW - Laboratory Hematology JF - Haematologica JO - Haematologica N2 - Ex vivo drug testing is a promising approach to identify novel treatment strategies for acute myeloid leukemia. However, accurate blast-specific drug responses cannot be measured with homogeneous "add-mix-measure" cell viability assays. In this study, we implemented a flow cytometry-based approach to simultaneously evaluate the ex vivo sensitivity of different cell populations in 34 primary acute myeloid leukemia samples to seven drugs and 27 rational drug combinations. Our data demonstrate that different cell populations present in acute myeloid leukemia samples have distinct sensitivity to targeted therapies. Particularly, blast cells of FAB M0/1 acute myeloid leukemia showed high sensitivity to venetoclax. In contrast, differentiated monocytic cells abundantly present in M4/5 subtypes showed resistance to Bcl-2 inhibition, whereas immature blasts in the same samples were sensitive, highlighting the importance of blast-specific readouts. Accordingly, in the total mononuclear cell fraction the highest BCL2/MCL1 gene expression ratio was observed in M0/1 and the lowest in M4/5 acute myeloid leukemia. Of the seven tested drugs, venetoclax had the highest blast-specific toxicity, and combining venetoclax with either MEK inhibitor trametinib or JAK inhibitor ruxolitinib effectively targeted all venetoclax-resistant blasts. In conclusion, we show that ex vivo efficacy of targeted agents and particularly Bcl-2 inhibitor venetoclax is influenced by the cell type, and accurate blast-specific drug responses can be assessed with a flow cytometry-based approach. SN - 1592-8721 UR - https://www.unboundmedicine.com/medline/citation/31296572/Phenotype-based_drug_screening_reveals_association_between_venetoclax_response_and_differentiation_stage_in_acute_myeloid_leukemia L2 - http://www.haematologica.org/cgi/pmidlookup?view=long&pmid=31296572 DB - PRIME DP - Unbound Medicine ER -