Bruton's tyrosine kinase is not essential for Bcr-Abl-mediated transformation of lymphoid or myeloid cells.
Bcr-Abl, a constitutively active tyrosine kinase, is the cause of chronic myeloid leukemia (CML) and a subset of acute lymphoblastic leukemias (ALL). Bruton's tyrosine kinase (BTK), a member of the Tec family of tyrosine kinases with a crucial role in B-cell development, is consistently tyrosine phosphorylated in Bcr-Abl expressing murine pre B cells. BTK has been implicated in Bcr-Abl-mediated B-cell transformation and resistance to imatinib, implying that inhibiting BTK may be therapeutically beneficial. We decided to test whether BTK is a critical node in Bcr-Abl transformation and potential drug target in imatinib-resistant Bcr-Abl-positive cells. We depleted BTK in Ba/F3 and 32D cells expressing native and kinase domain (KD) mutant (E255K and T315I) Bcr-Abl, using shRNA. BTK levels were reduced to <10% of controls. However, no differences in viability and cell proliferation were observed and the response to imatinib was not altered. Consistent with this, proliferation and viability were unaffected by inhibition of BTK with reversible (PC-005) and irreversible (PCI-31523) small molecule inhibitors. Lastly, BTK inhibition did not affect the ability of Bcr-Abl to transform primary murine hematopoietic cells in colony forming and B-cell transformation assays. Collectively this data argues against a critical role for BTK in Bcr-Abl-mediated leukemogenesis.
MacPartlin
M
M
Center for Hematologic Malignancies, Oregon Health & Science University Cancer Institute, Portland, OR 97239, USA.
Smith
A M
AM
Druker
B J
BJ
Honigberg
L A
LA
Deininger
M W
MW
D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D001549:Benzamides; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D016044:Fusion Proteins, bcr-abl / Q000502:physiology*; D006801:Humans; D000068877:Imatinib Mesylate; D007938:Leukemia / Q000209:etiology*; D008214:Lymphocytes / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D022423:Myeloid Cells / Q000473:pathology*; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D011743:Pyrimidines / Q000494:pharmacology
D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse; D016044:Fusion Proteins, bcr-abl