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  • Estupiñán, H. Yesid, et al. (författare)
  • BTK gatekeeper residue variation combined with cysteine 481 substitution causes super-resistance to irreversible inhibitors acalabrutinib, ibrutinib and zanubrutinib
  • 2021
  • Ingår i: Leukemia. - : Nature Publishing Group. - 0887-6924 .- 1476-5551.
  • Tidskriftsartikel (refereegranskat)abstract
    • Irreversible inhibitors of Bruton tyrosine kinase (BTK), pioneered by ibrutinib, have become breakthrough drugs in the treatment of leukemias and lymphomas. Resistance variants (mutations) occur, but in contrast to those identified for many other tyrosine kinase inhibitors, they affect less frequently the “gatekeeper” residue in the catalytic domain. In this study we carried out variation scanning by creating 11 substitutions at the gatekeeper amino acid, threonine 474 (T474). These variants were subsequently combined with replacement of the cysteine 481 residue to which irreversible inhibitors, such as ibrutinib, acalabrutinib and zanubrutinib, bind. We found that certain double mutants, such as threonine 474 to isoleucine (T474I) or methionine (T474M) combined with catalytically active cysteine 481 to serine (C481S), are insensitive to ≥16-fold the pharmacological serum concentration, and therefore defined as super-resistant to irreversible inhibitors. Conversely, reversible inhibitors showed a variable pattern, from resistance to no resistance, collectively demonstrating the structural constraints for different classes of inhibitors, which may affect their clinical application.
  • Ferrer, Anna, et al. (författare)
  • Different gene expression in immunoglobulin-mutated and immunoglobulin-unmutated forms of chronic lymphocytic leukemia.
  • 2004
  • Ingår i: Cancer Genetics and Cytogenetics. - : Elsevier. - 0165-4608. ; 153:1, s. 69-72
  • Tidskriftsartikel (refereegranskat)abstract
    • The mutation status of the immunoglobulin heavy chain variable regions (IgVH) has been found to be a good prognostic indicator for B-cell chronic lymphocytic leukemia (CLL) because unmutated VH genes are associated with rapid disease progression and shorter survival time. To study the differences in gene expression between the Ig-unmutated and Ig-mutated CLL subtypes, we performed gene expression profiling on 31 CLL cases and investigated the VH gene mutation status by sequencing. The array data showed that the greatest variances between the unmutated (20 cases) and the mutated (11 cases) group were in expressions of ZAP70, RAF1, PAX5, TCF1, CD44, SF1, S100A12, NUP214, DAF, GLVR1, MKK6, AF4, CX3CR1, NAFTC1, and HEX. ZAP70 was significantly more expressed in the Ig-unmutated CLL group, whereas the expression of all the other genes was higher in the Ig-mutated cases. These results corroborate a recent finding, according to which the expression of ZAP70 can predict the VH mutation status and suggest that RAF1, PAX5, and other differentially expressed genes may offer good markers for differentiating unmutated cases from mutated cases and thus serve as prognostic markers.
  • Hansson, H, et al. (författare)
  • Intermolecular interactions between the SH3 domain and the proline-rich TH region of Bruton's tyrosine kinase
  • 2001
  • Ingår i: FEBS Letters. - : Wiley-Blackwell. - 1873-3468 .- 0014-5793. ; 489:1, s. 67-70
  • Tidskriftsartikel (refereegranskat)abstract
    • The SH3 domain of Bruton's tyrosine kinase (Btk) is preceded by the Tec homology (TH) region containing proline-rich sequences. We have studied a protein fragment containing both the Btk SH3 domain and the proline-rich sequences of the TH region (PRR-SH3). Intermolecular NMR cross-relaxation measurements, gel permeation chromatography profiles, titrations with proline-rich peptides, and N-15 NMR relaxation measurements are all consistent with a monomer-dimer equilibrium with a dissociation constant on the order of 60 muM. The intermolecular interactions do, at least in part, involve proline-rich sequences in the TH region. This behavior of Btk PRR-SH3 may have implications for the functional action of Btk. (C) 2001 Federation of European Biochemical Societies. Published by Elsevier Science B.V. All rights reserved.
  • Hansson, H, et al. (författare)
  • Solution structure of the SH3 domain from Bruton's tyrosine kinase
  • 1998
  • Ingår i: Biochemistry. - : The American Chemical Society (ACS). - 0006-2960. ; 37:9, s. 2912-2924
  • Tidskriftsartikel (refereegranskat)abstract
    • X-linked agammaglobulinemia (XLA) is a heritable immunodeficiency caused by mutations in the gene coding for Bruton's tyrosine kinase (Btk). Btk belongs to the Tec family of tyrosine kinases. Each member of the family contains five regions and mutations causing XLA have been isolated in all five regions. We have determined the solution structure of the Src homology 3 (SH3) domain of Btk using two-and three-dimensional nuclear magnetic resonance (NMR) spectroscopy on natural abundance and N-15-labeled protein material. The structure determination is complemented by investigation of backbone dynamics based on N-15 NMR relaxation. The Btk SH3 forms a well-defined structure and shows the typical SH3 topology of two shea antiparallel beta-sheets packed almost perpendicular to each other in a sandwich-like fold. The N- and C-termini are more flexible as are peptide fragments in the RT and n-Src loops. The studied Btk SH3 fragment adopts two slowly interconverting conformations with a relative concentration ratio of 7:1. The overall fold of the minor form is similar to that of the major form, as judged on the basis of observed NOE connectivities and small chemical shift differences. A tryptophan (W251) ring flip is the favored mechanism for interconversion, although other possibilities cannot be excluded. The side chain of Y223, which becomes autophosphorylated upon activation of Btk, is exposed within the potential SH3 ligand binding site. Finally, we compare the present Btk SH3 structure with other SH3 structures.
  • Holinski-Feder, E, et al. (författare)
  • Mutation screening of the BTK gene in 56 families with X-linked agammaglobulinemia (XLA): 47 unique mutations without correlation to clinical course
  • 1998
  • Ingår i: Pediatrics. - : American Academy of Pediatrics. - 1098-4275. ; 101:2, s. 276-284
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives. To determine the utility of single-stranded conformation polymorphism (SSCP) analysis for mutation screening in the BTK (Bruton's tyrosine kinase) gene, we investigated 56 X-linked agammaglobulinemia (XLA) families. To obtain genotype/ phenotype correlations, predicted protein aberrations were correlated with the clinical course of the disease. Patients. This study included 56 patients with XLA, with or without a positive family history, who were diagnosed on the basis of their clinical features, low peripheral B-cell count, and low immunoglobulin levels. Ten patients with isolated hypogammaglobulinemia and 50 healthy males served as controls. Methods. SSCP analysis was performed for the entire BTK gene, including the exon-intron boundaries and the promoter region. Structural implications of the missense mutations were investigated by molecular modeling, and the functional consequences of some mutations also were evaluated by in vitro kinase assays and Western blot analysis. Results. We report the largest series of patients with XLA to date. All but 5 of the 56 index patients with XLA screened with SSCP analysis showed BTK gene abnormalities, and in 2 of the 5 SSCP-negative patients, no BTK protein was found by Western blot analysis. There were 51 mutations, including 37 novel ones, distributed across the entire gene. This report contains the first promoter mutation as well as 14 novel missense mutations with the first ones described for the Tec homology domain and the glycine-rich motif in the SH1 domain. Each index patient had a different mutation, except for four mutations, each in two unrelated individuals. This result supports the strong tendency for private mutations in this disease. No mutations were found in the controls. Conclusions. Our results demonstrate that molecular genetic testing by SSCP analysis provides an accurate tool for the definitive diagnosis of XLA and the discrimination of borderline cases, such as certain hypogammaglobulinemia or common variable immunodeficiency patients with overlapping clinical features. Genotype/phenotype correlations are not currently possible, making prediction of the clinical course based on molecular genetic data infeasible.
  • Hyytinen, Eija-R, et al. (författare)
  • Pattern of somatic androgen receptor gene mutations in patients with hormone-refractory prostate cancer.
  • 2002
  • Ingår i: Laboratory Investigation. - : Nature Publishing Group. - 1530-0307 .- 0023-6837. ; 82:11, s. 1591-1598
  • Tidskriftsartikel (refereegranskat)abstract
    • Progression to hormone-refractory growth of prostate cancer has been suggested to be mediated by androgen receptor (AR) gene alterations. We analyzed AR for mutations and amplifications in 21 locally recurrent prostate carcinomas treated with orchiectomy, estrogens, or a combination of orchiectomy and estramustine phosphate using fluorescence in situ hybridization, single-strand conformation polymorphism, and DNA sequence analyses. Amplification was observed in 4 of 16 (25%) and amino acid changing mutations was observed in 7 of 21 (33%) of the tumors, respectively. Two (50%) tumors with AR amplification also had missense mutation of the gene. Four of five (80%) cancers that were treated with a combination of orchiectomy and estramustine phosphate had a mutation clustered at codons 514 to 533 in the N-terminal domain of AR. In functional studies, these mutations did not render AR more sensitive to testosterone, dihydrotestosterone, androstenedione, or beta-estradiol. Tumors treated by orchiectomy had mutations predominantly in the ligand-binding domain. In summary, we found molecular alterations of AR in more than half of the prostate carcinomas that recurred locally. Some tumors developed both aberrations, possibly enhancing the cancer cell to respond efficiently to low levels of androgens. Furthermore, localization of point mutations in AR seems to be influenced by the type of treatment.
  • Knapp, S, et al. (författare)
  • Thermal unfolding of small proteins with SH3 domain folding pattern
  • 1998
  • Ingår i: Proteins. - : John Wiley and Sons Inc.. - 0887-3585 .- 1097-0134. ; 31:3, s. 309-319
  • Tidskriftsartikel (refereegranskat)abstract
    • The thermal unfolding of three SH3 domains of the Tec family of tyrosine kinases was studied by differential scanning calorimetry and CD spectroscopy, The unfolding transition of the three protein domains in the acidic pH region can be described as a reversible two-state process. For all three SH3 domains maximum stability was observed in the pH region 4.5 < pH < 7.0 where these domains unfold at temperatures of 353K (Btk), 342K (Itk), and 344K (Tec), At these temperatures an enthalpy change of 196 kJ/mol, 178 kJ/mol, and 169 kJ/mol was measured for Btk-, Itk-, and Tec-SH3 domains, respectively. The determined changes in heat capacity between the native and the denatured state are in an usual range expected for small proteins. Our analysis revealed that all SH3 domains studied are only weakly stabilized and have free energies of unfolding which do not exceed 12-16 kJ/mol but show quite high melting temperatures. Comparing unfolding free energies measured for eukaryotic SH3 domains with those of the topologically identical Sso7d protein from the hyperthermophile Sulfolobus solfataricus, the increased melting temperature of the thermostable protein is due to a broadening as well as a significant lifting of its stability curve. However, at their physiological temperatures, 310K for mesophilic SH3 domains and 350K for Sso7d, eukaryotic SH3 domains and Sso7d show very similar stabilities. (C) 1998 Wiley-Liss, Inc.
  • Kohonen-Corish, Maija R J, et al. (författare)
  • How to catch all those mutations--the report of the third Human Variome Project Meeting, UNESCO Paris, May 2010.
  • 2010
  • Ingår i: Human Mutation. - : John Wiley and Sons Inc.. - 1059-7794 .- 1098-1004. ; 31:12, s. 1374-1381
  • Tidskriftsartikel (refereegranskat)abstract
    • The third Human Variome Project (HVP) Meeting "Integration and Implementation" was held under UNESCO Patronage in Paris, France, at the UNESCO Headquarters May 10-14, 2010. The major aims of the HVP are the collection, curation, and distribution of all human genetic variation affecting health. The HVP has drawn together disparate groups, by country, gene of interest, and expertise, who are working for the common good with the shared goal of pushing the boundaries of the human variome and collaborating to avoid unnecessary duplication. The meeting addressed the 12 key areas that form the current framework of HVP activities: Ethics; Nomenclature and Standards; Publication, Credit and Incentives; Data Collection from Clinics; Overall Data Integration and Access-Peripheral Systems/Software; Data Collection from Laboratories; Assessment of Pathogenicity; Country Specific Collection; Translation to Healthcare and Personalized Medicine; Data Transfer, Databasing, and Curation; Overall Data Integration and Access-Central Systems; and Funding Mechanisms and Sustainability. In addition, three societies that support the goals and the mission of HVP also held their own Workshops with the view to advance disease-specific variation data collection and utilization: the International Society for Gastrointestinal Hereditary Tumours, the Micronutrient Genomics Project, and the Neurogenetics Consortium.
  • Lamminmaki, U, et al. (författare)
  • Structural analysis of an anti-estradiol antibody
  • 1997
  • Ingår i: Molecular Immunology. - : Pergamon. - 1872-9142 .- 0161-5890. ; 34:16-17, s. 1215-1226
  • Tidskriftsartikel (refereegranskat)abstract
    • An anti-estradiol antibody with improved specificity is searched for by combining steroid analog binding studies, mutant antibodies obtained from a phage-display library and structural modeling. Three-dimensional models for the anti-estradiol antibody 57-2 were constructed by comparative model building. Estradiol and analogs were docked into the combining site and molecular dynamics simulation was used to further refine this area of the protein. Cross-reactivities measured against 36 steroid analogs were used to help in the docking process and to evaluate the models. The roles of a number of residues were assessed by characterization of cross-reactivity mutants obtained from a phage display library. The cross-reactivity data and the results observed for mutants are explained by the structural model, in which the estradiol D-ring inserts deeply into the binding site and interacts with the antibody through at least one specific hydrogen bond. The binding data strongly suggest that this hydrogen bond connects the estradiol 17-hydroxyl group with the side chain of Gin H35. As expected for the binding of a small aromatic molecule, the antibody binding site contains many aromatic residues, e.g. Trp H50, H95 and L96 and Tyr L32, L49 and Phe L91. (C) 1997 Published by Elsevier Science Ltd. All rights reserved.
  • Lindvall, Jessica M, et al. (författare)
  • Bruton's tyrosine kinase: cell biology, sequence conservation, mutation spectrum, siRNA modifications, and expression profiling.
  • 2005
  • Ingår i: Immunological Reviews. - : Wiley-Blackwell Publishing Ltd. - 1600-065X .- 0105-2896. ; 203, s. 200-215
  • Forskningsöversikt (refereegranskat)abstract
    • Bruton's tyrosine kinase (Btk) is encoded by the gene that when mutated causes the primary immunodeficiency disease X-linked agammaglobulinemia (XLA) in humans and X-linked immunodeficiency (Xid) in mice. Btk is a member of the Tec family of protein tyrosine kinases (PTKs) and plays a vital, but diverse, modulatory role in many cellular processes. Mutations affecting Btk block B-lymphocyte development. Btk is conserved among species, and in this review, we present the sequence of the full-length rat Btk and find it to be analogous to the mouse Btk sequence. We have also analyzed the wealth of information compiled in the mutation database for XLA (BTKbase), representing 554 unique molecular events in 823 families and demonstrate that only selected amino acids are sensitive to replacement (P < 0.001). Although genotype-phenotype correlations have not been established in XLA, based on these findings, we hypothesize that this relationship indeed exists. Using short interfering-RNA technology, we have previously generated active constructs downregulating Btk expression. However, application of recently established guidelines to enhance or decrease the activity was not successful, demonstrating the importance of the primary sequence. We also review the outcome of expression profiling, comparing B lymphocytes from XLA-, Xid-, and Btk-knockout (KO) donors to healthy controls. Finally, in spite of a few genes differing in expression between Xid- and Btk-KO mice, in vivo competition between cells expressing either mutation shows that there is no selective survival advantage of cells carrying one genetic defect over the other. We conclusively demonstrate that for the R28C-missense mutant (Xid), there is no biologically relevant residual activity or any dominant negative effect versus other proteins.
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