Response to Bruton’s tyrosine kinase inhibitors in aggressive lymphomas linked to chronic selective autophagy
James D. PhelanSebastian ScheichJaewoo ChoiGeorge W. WrightBjörn HäuplRyan M. YoungSara A. RiekeMartine PapeYanlong JiHenning UrlaubArnold BolomskyCarmen DoebeleAlena ZindelTanja WotapekMonica KasbekarBrett CollingeDa Wei HuangZana CoulibalyVivian M. MorrisXiaoxuan ZhuangJulius C. EnßleXin YuWeihong XuYandan YangHong ZhaoZhuo WangAndy D. TranChristopher J. ShoemakerGalina ShevchenkoDaniel J. HodsonArthur L. ShafferLouis M. StaudtThomas Oellerich
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The aim of this study is to analyze the scientific literature data on the frequency and characteristics of infectious complications during the treatment of patients with lymphoproliferative diseases with a new class of drugs, selective inhibitors of Brutons tyrosine kinase (BTK). This work describes the indications for appointing these drugs as well as the participation of BTK in the development and activation of B cells. We have studied the main characteristics of BTK inhibitors used in clinical practice and associated disorders in the activity of off-target tyrosine kinases. The work describes the main types of known infectious complications developing during the treatment with the drugs of this group, the period of their appearance, and characteristic pathogens.
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KEYWORDS: AnaphylaxisbasophilsBruton's tyrosine kinase (BTK)desensitizationhypersensitivityibrutinibimmunotherapymast cells
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Imatinib Mesylate
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breakpoint cluster region
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Loss of function of Bruton's tyrosine kinase (Btk) results in X-linked immunodeficiencies characterized by a broad spectrum of signaling defects, including those dependent on Src family kinase-linked cell surface receptors. A gain-of-function mutant, Btk*, induces the growth of fibroblasts in soft agar and relieves the interleukin-5 dependence of a pre-B-cell line. To genetically define Btk signaling pathways, we used a strategy to either activate or inactivate Src family kinases in fibroblasts that express Btk*. The transformation potential of Btk* was dramatically increased by coexpression with a partly activated c-Src mutant (E-378 --> G). This synergy was further potentiated by deletion of the Btk Src homology 3 domain. Downregulation of Src family kinases by the C-terminal Src kinase (Csk) suppressed Btk* activation and biological potency. In contrast, kinase-inactive Csk (K-222 --> R), which functioned as a dominant negative molecule, synergized with Btk* in biological transformation. Activation of Btk* correlated with increased phosphotyrosine on transphosphorylation and autophosphorylation sites. These findings suggest that the Src and Btk kinase families form specific signaling units in tissues in which both are expressed.
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The members of the Tec family of tyrosine kinases contain Src homology 2 (SH2), SH3, and pleckstrin homology (PH) domains, in addition to their kinase domains. Unlike the Src family of tyrosine kinases, which have a negative regulatory tyrosine located at their COOH-termini, members of the Tec family do not have an obvious negative regulatory site. Liu et al. (News and Views by Koyasu) have now identified a protein, termed IBtk, that interacts with and inhibits Bruton's tyrosine kinase (Btk) activity. IBtk and Btk associated in vitro and in vivo; however, IBtk did not interact with the related Tec family kinase Itk, suggesting that IBtk might specifically interact with Btk. Chicken B cells transfected with IBtk exhibited reduced changes of calcium concentrations and inhibition of NF-κB activation, in response to B cell-receptor stimulation. Other experiments revealed that the COOH-terminal portion of IBtk bound the the PH domain of Btk, and was responsible for mediating the inhibtion of Btk activity. Activation of B cells led to the localization of Btk and IBtk to the plasma membrane, which suggests that IBtk might inhibit Btk activity soon after B cell receptor-dependent activation to tightly control Btk-mediated signaling. These data are likely to spur a search for specific inhibitors of other Tec family members. W. Liu, I. Quinto, X. Chen, C. Palmieri, R. L. Rabin, O. M. Schwartz, D. L. Nelson, G. Scala, Direct inhibition of Bruton's tyrosine kinase by IBtk, a Btk-binding protein. Nature Immunol. 2 , 939-946 (2001). [Online Journal] S. Koyasu, Beating a kinase? Nature Immunol. 2 , 897-898 (2001). [Online Journal]
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Summary To elucidate their mechanism of action, inhibitors of Bruton tyrosine kinase ( BTK ) and resistant BTK mutants were employed to dissect target‐dependent cellular functions. BTK ‐C481S and ‐T474I, expressed in Ramos and NALM ‐6 cells, maintained BTK auto‐phosphorylation under treatment with ibrutinib or dasatinib, respectively, which showed only modest cytotoxicity. Retained activity of BTK ‐T474 partially rescued cell migration from inhibition by dasatinib. Importantly, resistant BTK mutants reconstituted B cell receptor‐triggered chemokine secretion in the presence of corresponding inhibitors, demonstrating that BTK activity is connected with cell‐intrinsic functions of malignant B cells with importance for their dialogue with the micro‐environment.
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Bruton's tyrosine kinase (Btk) is a recently described B-cell-specific tyrosine kinase. Mutations in this gene lead to human X chromosome-linked agammaglobulinemia and murine X-linked immunodeficiency. Although genetic evidence strongly suggests that Btk plays a crucial role in B-lymphocyte differentiation and activation, its precise mechanism of action remains unknown, primarily because the proteins that it interacts with have not yet been identified. Here, we show that Btk interacts with Src homology 3 domains of Fyn, Lyn, and Hck, protein-tyrosine kinases that get activated upon stimulation of B- and T-cell receptors. These interactions are mediated by two 10-aa motifs in Btk. An analogous site with the same specificity is also present in Itk, the T-cell-specific homologue of Btk. Our data extend the range of interactions mediated by Src homology 3 domains and provide an indication of a link between Btk and established signaling pathways in B lymphocytes.
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Src family kinase
Tyrosine-protein kinase CSK
X-linked agammaglobulinemia
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