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Patient-derived acute myeloid leukemia (AML) bone marrow cells display distinct intracellular kinase phosphorylation patterns

Original Research

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Authors: Keith Shults, Leanne Flye, Lisa Green, Thomas Daly, et al.

Published Date May 2009 Volume 2009:1 Pages 49 - 59
DOI: http://dx.doi.org/10.2147/CMAR.S5611

Keith Shults1, Leanne Flye1, Lisa Green2, Thomas Daly2, Jason R Manro2, Michael Lahn2

1Esoterix, Brentwood, TN, USA; 2Eli Lilly and Company, Lilly Research Laboratories, Indianapolis, IN, USA

Abstract: Multiparametric analyses of phospho-protein activation in patients with acute myeloid leukemia (AML) offers a quantitative measure to monitor the activity of novel intracellular kinase (IK) inhibitors. As recent clinical investigation with FMS-like tyrosine-3 inhibitors demonstrated, targeting IK with selective inhibitors can have a modest clinical benefit. Because multiple IKs are active in patients with AML, multikinase inhibitors may provide the necessary inhibition profile to achieve a more sustained clinical benefit. We here describe a method of assessing the activation of several IKs by flow cytometry. In 40 different samples of patients with AML we observed hyper-activated phospho-proteins at baseline, which is modestly increased by adding stem cell factor to AML cells. Finally, AML cells had a significantly different phospho-protein profile compared with cells of the lymphocyte gate. In conclusion, our method offers a way to determine the activation status of multiple kinases in AML and hence is a reliable assay to evaluate the pharmacodynamic activity of novel multikinase inhibitors.

Keywords: leukemia, AML, bone marrow, flow cytometry






 

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