In:
Blood, American Society of Hematology, Vol. 110, No. 11 ( 2007-11-16), p. 1015-1015
Abstract:
Background: Bruton’s tyrosine kinase (BTK) is a member of the Tec family of protein tyrosine kinases. Mutations of BTK have been associated with a block in B cell development, and are causal to X-linked agammaglobulinemia (XLA) in humans. Bcr-Abl is a constitutively active tyrosine kinase that is essential for the transforming capacity of Bcr-Abl. Using phosphoproteomics we have shown that BTK is consistently tyrosine phosphorylated in Bcr-Abl expressing Ba/F3 cells [Griswold et al. Mol Cell Biol.2006;26(16):6082–93.]. Since BTK has also been implicated in resistance to imatinib [Hofmann et al. Lancet2002;359(9305):481–6] and one study [Feldhahn et al. J Exp Med.2005; 201(11):1837–52] had suggested a role of BTK in Bcr-Abl-induced transformation we decided to test whether BTK may be a critical node in Bcr-Abl transformation and potential drug target in imatinib-resistant Bcr-Abl-positive cells. Results: 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, but no differences in viability and cell proliferation were observed. Additionally, responses to imatinib were not affected by BTK depletion. We further tested the effects of reversible (PCI-33918) and irreversible (PCI-31523) small molecule inhibitors of BTK on the above cell lines as well as human Ph+ B-lymphoblastic lines. Selective BTK inhibition did not impact cell proliferation. Lastly, BTK inhibition had no effect on Bcr-Abl-mediated transformation of primary murine hematopoietic cells in colony forming assays. Conclusion: Despite the fact the BTK is consistently tyrosine phosophorylated in Bcr-Abl expressing cells, our data suggests it is not essential for Bcr-Abl-mediated transformation of lymphoid or myeloid cells.
Type of Medium:
Online Resource
ISSN:
0006-4971
,
1528-0020
DOI:
10.1182/blood.V110.11.1015.1015
Language:
English
Publisher:
American Society of Hematology
Publication Date:
2007
detail.hit.zdb_id:
1468538-3
detail.hit.zdb_id:
80069-7
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