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

Heikki Kuusanmäki, Aino-Maija Leppä, Petri Pölönen, Mika Kontro, Olli Dufva, Debashish Deb, Bhagwan Yadav, Oscar Bruck, Ashwini Kumar, Hele Everaus, Bjorn Tore Gjertsen, Merja Heinäniemi, Kimmo Porkka, Satu Mustjoki, Caroline A. Heckman

Forskningsoutput: TidskriftsbidragArtikelVetenskapligPeer review

Sammanfattning

Ex vivo drug testing is a promising approach to identify novel treatment strategies for acute myeloid leukemia (AML). 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 AML samples to seven drugs and 27 rational drug combinations. Our data demonstrate that different cell populations present in AML samples have distinct sensitivity to targeted therapies. Particularly, blast cells of FAB M0/1 AML 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 AML. 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.

Originalspråkengelska
TidskriftHaematologica
Volym105
Utgåva3
Sidor (från-till)708-720
Antal sidor13
ISSN0390-6078
DOI
StatusPublicerad - 1 mar 2020
MoE-publikationstypA1 Tidskriftsartikel-refererad

Vetenskapsgrenar

  • 3122 Cancersjukdomar

Citera det här