The bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) blocks hairy cell leukaemia survival, proliferation and B cell receptor signalling: a new therapeutic approach.
B cell receptor (BCR) signalling plays a critical role in the progression of several B-cell malignancies, but its role in hairy cell leukaemia (HCL) is ambiguous. Bruton tyrosine kinase (BTK), a key player in BCR signalling, as well as B cell migration and adhesion, can be targeted with ibrutinib, a selective, irreversible BTK inhibitor. We analysed BTK expression and function in HCL and analysed the effects of ibrutinib on HCL cells. We demonstrated uniform BTK protein expression in HCL cells. Ibrutinib significantly inhibited HCL proliferation and cell cycle progression. Accordingly, ibrutinib also reduced HCL cell survival after BCR triggering with anti-immunoglobulins and abrogated the activation of kinases downstream of the BCR (PI3K and MAPK). Ibrutinib also inhibited BCR-dependent secretion of the chemokines CCL3 and CCL4 by HCL cells. Interestingly, ibrutinib inhibited also CXCL12-induced signalling, a key pathway for bone marrow homing. Collectively, our data support the clinical development of ibrutinib in patients with HCL.
Department of Leukemia, M. D. Anderson Cancer Center, The University of Texas, Houston, TX, USA.
Mariela
M
Sivina
Robert J
RJ
Kreitman
Evgeny
E
Arons
Farhad
F
Ravandi
Jan A
JA
Burger
D000225:Adenine / Q000031:analogs & derivatives; D000328:Adult; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D054405:Chemokine CCL3 / Q000378:metabolism; D054407:Chemokine CCL4 / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D006801:Humans; D007943:Leukemia, Hairy Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology*; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C515429:CCL3 protein, human; C066507:CCL4 protein, human; C515255:CXCL12 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D054377:Chemokine CXCL12; D009363:Neoplasm Proteins; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D011947:Receptors, Antigen, B-Cell; C551803:ibrutinib; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D000225:Adenine
B cell receptor; bruton tyrosine kinase; hairy cell leukaemia; ibrutinib; microenvironment