title: Targeting BTK for the treatment of FLT3-ITD mutated acute myeloid leukemia.
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.
authors: Department of Molecular Haematology, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, United Kingdom.
authors: Genevra
authors: G
authors: Pillinger
authors: Department of Molecular Haematology, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, United Kingdom.
authors: Amina
authors: A
authors: Abdul-Aziz
authors: Department of Molecular Haematology, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, United Kingdom.
authors: Lyubov
authors: L
authors: Zaitseva
authors: Department of Haematology, Norfolk and Norwich University Hospitals NHS Trust, Colney Lane, Norwich, NR4 7UY, United Kingdom.
authors: Matthew
authors: M
authors: Lawes
authors: Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3GE, United Kingdom.
authors: David J
authors: DJ
authors: MacEwan
authors: Department of Molecular Haematology, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, United Kingdom.|Department of Haematology, Norfolk and Norwich University Hospitals NHS Trust, Colney Lane, Norwich, NR4 7UY, United Kingdom.
authors: Kristian M
authors: KM
authors: Bowles
authors: Department of Molecular Haematology, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, United Kingdom.
authors: Stuart A
authors: SA
authors: Rushworth
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D017209:Apoptosis / Q000187:drug effects; D001752:Blast Crisis / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003630:Daunorubicin / Q000494:pharmacology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D010880:Piperidines; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051941:fms-Like Tyrosine Kinase 3 / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D034741:RNA, Small Interfering; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D051941:fms-Like Tyrosine Kinase 3; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D000225:Adenine; D003630:Daunorubicin