A transducer module consisting of Toll-like receptor 9 and Bruton's tyrosine kinase triggers acute myeloid leukemia blast proliferation.

Acute myeloid leukemia (AML) is a genetically heterogeneous disease and mutations occur in various genes including those encoding for signaling molecules. A well characterized example is the tyrosine kinase Flt3, which harbours internal tandem duplications in about one third of AML patients that render the kinase constitutively active. AML cells often become addicted to such constitutively activated survival inducing signaling pathways that can be therapeutically exploited by using small molecule kinase inhibitors. By screening bone marrow biopsies of AML patients for kinase expression profiles, we detected Bruton9s tyrosine kinase (Btk) in AML blasts in 26 out of 30 analyzed cases. Btk acts as an oncogene in chronic lymphocytic leukemia as well as in certain B-cell lymphoma subtypes. As compared to diseases of lymphoid origin far less is known about the role of Btk in myeloid neoplasias. Here, we show that Btk is often constitutively activated in AML and moreover, that genetic as well as pharmacological inhibition of Btk in AML cell lines as well as primary patient-derived AML cultures strongly diminishes AML cell growth. By applying quantitative mass spectrometry, we identified a signalosome consisting of Btk and Toll-like receptor 9 that is needed to constitutively transduce proliferation signals through the NFkB pathway. This newly identified TLR9/Btk signaling axis is of clinical interest as it is effectively druggable by Btk inhibitors which have so far only indications for the treatment of lymphoid malignancies. Citation Format: Thomas Oellerich, Sebastian Mohr, Hanibal Bohnenberger, Anjali Dubey, Silvia Munch, Johannes Wicht, Mark F. Oellerich, Christina Perske, Gesine Bug, Philipp Strobel, Henning Urlaub, Hubert Serve. A transducer module consisting of Toll-like receptor 9 and Bruton9s tyrosine kinase triggers acute myeloid leukemia blast proliferation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4203. doi:10.1158/1538-7445.AM2014-4203