title: Identification of Bruton's tyrosine kinase as a therapeutic target in acute myeloid leukemia.
abstract: Bruton's tyrosine kinase (BTK) is a cytoplasmic protein found in all hematopoietic cell lineages except for T cells. BTK mediates signaling downstream of a number of receptors. Pharmacologic targeting of BTK using ibrutinib (previously PCI-32765) has recently shown encouraging clinical activity in a range of lymphoid malignancies. This study reports for the first time that ibrutinib inhibits blast proliferation from human acute myeloid leukemia (AML) and that treatment with ibrutinib significantly augmented cytotoxic activities of standard AML chemotherapy cytarabine or daunorubicin. Here we describe that BTK is constitutively phosphorylated in the majority of AML samples tested, with BTK phosphorylation correlating highly with the cell's cytotoxic sensitivity toward ibrutinib. BTK-targeted RNAi knockdown reduced colony-forming capacity of primary AML blasts and proliferation of AML cell lines. We showed that ibrutinib binds at nanomolar range to BTK. Furthermore, we showed ibrutinib's antiproliferative effects in AML are mediated via an inhibitory effect on downstream nuclear factor-κB survival pathways. Moreover, ibrutinib inhibited AML cell adhesion to bone marrow stroma. Furthermore, these effects of ibrutinib in AML were seen at comparable concentrations efficacious in chronic lymphocytic leukemia. These results provide a biological rationale for clinical evaluation of BTK inhibition in AML patients.
authors.affiliation: Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, United Kingdom;
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Rushworth
authors.forename: Megan Y
authors.initials: MY
authors.lastname: Murray
authors.forename: Lyubov
authors.initials: L
authors.lastname: Zaitseva
authors.forename: Kristian M
authors.initials: KM
authors.lastname: Bowles
authors.forename: David J
authors.initials: DJ
authors.lastname: MacEwan
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000328:Adult; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D008297:Male; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D010880:Piperidines; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
chemical_list: D016328:NF-kappa B; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D000225:Adenine