Targeting BTK for the treatment of FLT3-ITD mutated acute myeloid leukemia

Pillinger, Genevra, Abdul-Aziz, Amina, Zaitseva, Lyubov, Lawes, Matt, MacEwan, David, Bowles, Kristian and Rushworth, Stuart (2015) Targeting BTK for the treatment of FLT3-ITD mutated acute myeloid leukemia. Scientific Reports, 5. ISSN 2045-2322

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Abstract

Approximately 20% of patients with acute myeloid leukaemia (AML) have a mutation in FMS-like-tyrosine-kinase-3 (FLT3). FLT3 is a trans-membrane receptor with a tyrosine kinase domain which, when activated, initiates a cascade of phosphorylated proteins including the SRC family of kinases. Recently our group and others have shown that pharmacologic inhibition and genetic knockdown of Bruton's tyrosine kinase (BTK) blocks AML blast proliferation, leukaemic cell adhesion to bone marrow stromal cells as well as migration of AML blasts. The anti-proliferative effects of BTK inhibition in human AML are mediated via inhibition of downstream NF-κB pro-survival signalling however the upstream drivers of BTK activation in human AML have yet to be fully characterised. Here we place the FLT3-ITD upstream of BTK in AML and show that the BTK inhibitor ibrutinib inhibits the survival and proliferation of FLT3-ITD primary AML blasts and AML cell lines. Furthermore ibrutinib inhibits the activation of downstream kinases including MAPK, AKT and STAT5. In addition we show that BTK RNAi inhibits proliferation of FLT3-ITD AML cells. Finally we report that ibrutinib reverses the cyto-protective role of BMSC on FLT3-ITD AML survival. These results argue for the evaluation of ibrutinib in patients with FLT3-ITD mutated AML.

Item Type: Article
Additional Information: This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
Uncontrolled Keywords: acute myeloid leukaemia,bruton's tyrosine kinase,flt3,flt3-itd,ibrutinib
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Pure Connector
Date Deposited: 25 Sep 2015 13:40
Last Modified: 22 Jul 2020 00:21
URI: https://ueaeprints.uea.ac.uk/id/eprint/54514
DOI: 10.1038/srep12949

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