From identification of the BTK kinase to effective management of leukemia.


:BTK is a cytoplasmic protein-tyrosine kinase, whose corresponding gene was isolated in the early 1990s. BTK was initially identified by positional cloning of the gene causing X-linked agammaglobulinemia and independently in a search for new kinases. Given the phenotype of affected patients, namely lack of B-lymphocytes and plasma cells with the ensuing inability to mount humoral immune responses, BTK inhibitors were anticipated to have beneficial effects on antibody-mediated pathologies, such as autoimmunity. In contrast to, for example, the SRC-family of cytoplasmic kinases, there was no obvious way in which structural alterations would yield constitutively active forms of BTK, and such mutations were also not found in leukemias or lymphomas. In 2007, the first efficient inhibitor, ibrutinib, was reported and soon became approved both in the United States and in Europe for the treatment of three B-cell malignancies, mantle cell lymphoma, chronic lymphocytic leukemia and Waldenström's macroglobulinemia. Over the past few years, additional inhibitors have been developed, with acalabrutinib being more selective, and recently demonstrating fewer clinical adverse effects. The antitumor mechanism is also not related to mutations in BTK. Instead tumor residency in lymphoid organs is inhibited, making these drugs highly versatile. BTK is one of the only 10 human kinases that carry a cysteine in the adenosine triphosphate-binding cleft. As this allows for covalent, irreversible inhibitor binding, it provides these compounds with a highly advantageous character. This quality may be crucial and bodes well for the future of BTK-modifying medicines, which have been estimated to reach annual multi-billion dollar sales in the future.






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  • FBXO10 deficiency and BTK activation upregulate BCL2 expression in mantle cell lymphoma.

    abstract::Targeting Bruton tyrosine kinase (BTK) by ibrutinib is an effective treatment for patients with relapsed/refractory mantle cell lymphoma (MCL). However, both primary and acquired resistance to ibrutinib have developed in a significant number of these patients. A combinatory strategy targeting multiple oncogenic pathwa...


    pub_type: 杂志文章


    authors: Li Y,Bouchlaka MN,Wolff J,Grindle KM,Lu L,Qian S,Zhong X,Pflum N,Jobin P,Kahl BS,Eickhoff JC,Wuerzberger-Davis SM,Miyamoto S,Thomas CJ,Yang DT,Capitini CM,Rui L

    更新日期:2016-12-01 00:00:00

  • DNA: leukemia's secret weapon of bone mass destruction.

    abstract::Interaction of tumour cells with their microenvironment impacts on all aspects of cancer, ranging from development through to treatment response. In this issue, Dvorak and colleagues(1) reveal a novel tumour/microenvironment relationship that may drive leukemia pathogenesis. Specifically, they find that leukemic cells...


    pub_type: 评论,杂志文章


    authors: Tait S

    更新日期:2013-10-31 00:00:00

  • Pim kinase-dependent inhibition of c-Myc degradation.

    abstract::Pim kinases are found to be highly expressed in leukemia, lymphoma, prostate and pancreatic cancer. Bitransgenic mice overexpressing either Pim-1 or Pim-2 and c-Myc succumb to pre-B-cell lymphoma at a strikingly accelerated speed. Despite that Pim-1/Pim-2 has long been recognized as a strong synergistic partner with c...


    pub_type: 杂志文章


    authors: Zhang Y,Wang Z,Li X,Magnuson NS

    更新日期:2008-08-14 00:00:00

  • The WIP1 oncogene promotes progression and invasion of aggressive medulloblastoma variants.

    abstract::Recent studies suggest that medulloblastoma, the most common malignant brain tumor of childhood, is comprised of four disease variants. The WIP1 oncogene is overexpressed in Group 3 and 4 tumors, which contain medulloblastomas with the most aggressive clinical behavior. Our data demonstrate increased WIP1 expression i...


    pub_type: 杂志文章


    authors: Buss MC,Remke M,Lee J,Gandhi K,Schniederjan MJ,Kool M,Northcott PA,Pfister SM,Taylor MD,Castellino RC

    更新日期:2015-02-26 00:00:00

  • Hypervariable allelic expression patterns of the imprinted IGF2 gene in tumor cells.

    abstract::The IGF2 gene, which encodes a growth factor, is subject to genomic imprinting. The frequently observed loss of IGF2 imprinting in a variety of tumors has been suggested to contribute to neoplasia. Since these reports have not documented the imprinting status of IGF2 at the cellular level, it cannot be excluded that t...


    pub_type: 杂志文章


    authors: He L,Cui H,Walsh C,Mattsson R,Lin W,Anneren G,Pfeifer-Ohlsson S,Ohlsson R

    更新日期:1998-01-08 00:00:00

  • Cytokine receptors and hematopoietic differentiation.

    abstract::Colony-stimulating factors and other cytokines signal via their cognate receptors to regulate hematopoiesis. In many developmental systems, inductive signalling determines cell fate and, by analogy with this, it has been postulated that cytokines, signalling via their cognate receptors, may play an instructive role in...


    pub_type: 杂志文章,评审


    authors: Robb L

    更新日期:2007-10-15 00:00:00

  • Genetic instability: tipping the balance.

    abstract::Tumor cells typically contain a genome that is highly divergent from the genome of normal, non-transformed cells. This genetic divergence is caused by a number of distinct changes that the tumor cell acquires during its transformation from a normal cell into a tumorigenic counterpart. Changes to the genome include mut...


    pub_type: 杂志文章,评审


    authors: Janssen A,Medema RH

    更新日期:2013-09-19 00:00:00

  • A combinatorial microRNA therapeutics approach to suppressing non-small cell lung cancer.

    abstract::Targeted cancer therapies, although often effective, have limited utility owing to preexisting primary or acquired secondary resistance. Consequently, agents are sometimes used in combination to simultaneously affect multiple targets. MicroRNA mimics are excellent therapeutic candidates because of their ability to rep...


    pub_type: 杂志文章


    authors: Kasinski AL,Kelnar K,Stahlhut C,Orellana E,Zhao J,Shimer E,Dysart S,Chen X,Bader AG,Slack FJ

    更新日期:2015-07-01 00:00:00

  • Molecular cloning and characterization of the t(2;14) translocation associated with childhood chronic lymphocytic leukemia.

    abstract::Two rare cases of chronic lymphocytic leukemia (CLL) in children, patients AS and LH, have been found to be associated with a unique chromosomal translocation, t(2;14)(p13;q32). Previous studies have shown the breakpoints of this translocation to be in the gamma 2 switch region of the Ig heavy-chain locus on chromosom...


    pub_type: 杂志文章


    authors: Richardson AL,Humphries CG,Tucker PW

    更新日期:1992-05-01 00:00:00

  • Transforming growth factor-beta 1 inhibits cyclin D1 expression in intestinal epithelial cells.

    abstract::Transforming growth factor-beta 1 (TGF-beta 1) inhibits most epithelial cell types by blocking cell cycle progression during the G1 phase. D cyclins are normally expressed during G1 and are regulators of G1 progression. One of the crucial functions of D cyclins is their ability to bind to a cyclin-dependent kinase (Cd...


    pub_type: 杂志文章


    authors: Ko TC,Sheng HM,Reisman D,Thompson EA,Beauchamp RD

    更新日期:1995-01-05 00:00:00

  • A human tumour-derived mutant p53 protein induces a p34cdc2 reversible growth arrest in fission yeast.

    abstract::We have expressed wild-type and human tumour-derived mutant p53 cDNA genes in the fission yeast Schizosaccharomyces pombe. In the case of one mutant this resulted in a growth arrest of recipient yeast cells. In contrast, wild-type p53 and three other mutant proteins tested did not block outgrowth of colonies. Human an...


    pub_type: 杂志文章


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  • Protein interactions at Sp1-like sites in the TGF alpha promoter as visualized by in vivo genomic footprinting.

    abstract::Transcription from the rat TGF alpha promoter initiates at two predominant sites (-188 and -58) in a G+C-rich region that does not contain TATA or CAAT motifs. Previous studies using transfected reporter constructs implicated the transcription factor Sp1 in active expression from the promoter, particularly from the -5...


    pub_type: 杂志文章


    authors: Chen X,Wright KL,Berkowitz EA,Azizkhan JC,Ting JP,Lee DC

    更新日期:1994-11-01 00:00:00

  • Unmasking by soluble IL-6 receptor of IL-6 effect on metastatic melanoma: growth inhibition and differentiation of B16-F10.9 tumor cells.

    abstract::Interleukin-6 (IL-6) inhibits the growth of melanocytes and of early stage melanoma cells, but not that of advanced melanoma cells. The in vitro IL-6 response can be restored in the highly metastatic melanoma B16-F10.9 by addition of recombinant soluble IL-6 receptor alpha-chain (sIL-6R). The F10.9 cells then undergo ...


    pub_type: 杂志文章


    authors: Oh JW,Katz A,Harroch S,Eisenbach L,Revel M,Chebath J

    更新日期:1997-07-31 00:00:00

  • Histone deacetylases and the immunological network: implications in cancer and inflammation.

    abstract::The initiation, magnitude and duration of an immune response against antigens are a tightly regulated process involving a dynamic, orchestrated balance of pro- and anti-inflammatory pathways in immune cells. Such a delicate balance is critical for allowing efficient immune response against foreign antigens while preve...


    pub_type: 杂志文章,评审


    authors: Villagra A,Sotomayor EM,Seto E

    更新日期:2010-01-14 00:00:00

  • LncFZD6 initiates Wnt/β-catenin and liver TIC self-renewal through BRG1-mediated FZD6 transcriptional activation.

    abstract::Liver tumor-initiating cells (TICs), the drivers for liver tumorigenesis, accounts for liver tumor initiation, metastasis, drug resistance and relapse. Wnt/β-catenin signaling pathway emerges as a critical modulator in liver TIC self-renewal. However, the molecular mechanism of Wnt/β-catenin initiation in liver tumori...


    pub_type: 杂志文章


    authors: Chen Z,Gao Y,Yao L,Liu Y,Huang L,Yan Z,Zhao W,Zhu P,Weng H

    更新日期:2018-06-01 00:00:00

  • TEAD1/4 exerts oncogenic role and is negatively regulated by miR-4269 in gastric tumorigenesis.

    abstract::TEA domain (TEAD) transcription factors are key components of the Hippo-YAP1 signaling pathway, but their functional role and regulatory mechanisms remain unclear. This study aims to comprehensively explore the expression pattern and functional role of TEAD family in gastric carcinogenesis and investigate its regulati...


    pub_type: 杂志文章


    authors: Zhou Y,Huang T,Zhang J,Wong CC,Zhang B,Dong Y,Wu F,Tong JHM,Wu WKK,Cheng ASL,Yu J,Kang W,To KF

    更新日期:2017-11-23 00:00:00

  • Oncogenic Ras-induced secretion of a novel inhibitor of skeletal myoblast differentiation.

    abstract::Expression of oncogenic H-Ras in 23A2 myoblasts (A2:H-Ras cells) is sufficient to induce both a transformed phenotype and a differentiation-defective phenotype. Because oncogenic Ras is known to induce the secretion of several different growth factors involved in maintaining the transformed phenotype of both fibroblas...


    pub_type: 杂志文章


    authors: Weyman CM,Wolfman A

    更新日期:1997-11-20 00:00:00

  • RFP represses transcriptional activation by bHLH transcription factors.

    abstract::Basic helix-loop-helix (bHLH) transcription factors play a pivotal role in the regulation of tumorigenesis, and also in a wide range of other developmental processes in diverse species from yeast to humans. Here we demonstrate for the first time that Ret finger protein (RFP), a member of the TRIM family of proteins in...


    pub_type: 杂志文章


    authors: Bloor AJ,Kotsopoulou E,Hayward P,Champion BR,Green AR

    更新日期:2005-10-13 00:00:00

  • Regulation of NF-kappaB activity by I kappaB-related proteins in adenocarcinoma cells.

    abstract::Constitutive NF-kappaB activity varies widely among cancer cell lines. In this report, we studied the expression and the role of different I kappaB inhibitors in adenocarcinoma cell lines. High constitutive NF-kappaB activity and low I kappaB-alpha expression was found in a number of these cell lines. Moreover, some o...


    pub_type: 杂志文章


    authors: Dejardin E,Deregowski V,Chapelier M,Jacobs N,Gielen J,Merville MP,Bours V

    更新日期:1999-04-22 00:00:00

  • Human T-cell leukemia virus type 1 Tax attenuates gamma-irradiation-induced apoptosis through physical interaction with Chk2.

    abstract::Checkpoint kinase 2 (Chk2) is known to mediate diverse cellular responses to genotoxic stress. The fundamental role of Chk2 is to regulate the network of genome-surveillance pathways that coordinate cell-cycle progression with DNA repair and cell survival or death. Defects in Chk2 contribute to the development of both...


    pub_type: 杂志文章


    authors: Park HU,Jeong SJ,Jeong JH,Chung JH,Brady JN

    更新日期:2006-01-19 00:00:00

  • Diet and cancer prevention.

    abstract::Dietary effects are presumed to underlie many of the large international differences in incidence seen for most cancers. Apart from alcohol and a few micronutrients, however, the role of specific nutritional factors remains ill-defined. The evidence for a role of energy balance, physical inactivity, and obesity has st...


    pub_type: 杂志文章,评审


    authors: McCullough ML,Giovannucci EL

    更新日期:2004-08-23 00:00:00

  • A variety of tumours induced by the middle T antigen of polyoma virus in a transgenic mouse family.

    abstract::A transgenic mouse family expressing the middle T antigen of polyoma virus under control of the immunoglobulin heavy chain (IgE) enhancer showed the frequent occurrence of carcinomas in various organs, predominantly in females. Most frequently affected were the salivary and thyroid glands, but mammary tumours, liver h...


    pub_type: 杂志文章


    authors: Rassoulzadegan M,Courtneidge SA,Loubière R,el Baze P,Cuzin F

    更新日期:1990-10-01 00:00:00

  • The amplicons in HL60 cells contain novel cellular sequences linked to MYC locus DNA.

    abstract::We have previously determined that the amplified DNA present in the HL60 promyelocytic leukaemia cell line contained 70 kb of continuous DNA sequences around the c-myc gene. In the work presented here we have further defined the HL60 amplicon and find it to be of the order of 160 kb and to contain a large region of DN...


    pub_type: 杂志文章


    authors: Feo S,Di Liegro C,Mangano R,Read M,Fried M

    更新日期:1996-10-03 00:00:00

  • c-Myc inhibits myogenic differentiation and myoD expression by a mechanism which can be dissociated from cell transformation.

    abstract::The c-Myc oncoprotein is a basic-helix-loop-helix-leucine zipper (b-HLH-LZ) transcription factor involved in regulating cell proliferation and differentiation. We have used retrovirus-mediated gene transfer to investigate the effect of ectopic c-Myc expression on the spontaneous differentiation of primary quail myobla...


    pub_type: 杂志文章


    authors: La Rocca SA,Crouch DH,Gillespie DA

    更新日期:1994-12-01 00:00:00

  • Analysis of the neurofibromatosis type 1 (NF1) GAP-related domain by site-directed mutagenesis.

    abstract::The gene for von Recklinghausen neurofibromatosis type 1 (NF1) was recently identified by positional cloning and found to encode a protein with sequence similarity to a family of eucaryotic GTPase-activating proteins (GAPs). Expression of the NF1-GAP-related domain (NF1GRD) has been shown to complement yeast strains d...


    pub_type: 杂志文章


    authors: Gutmann DH,Boguski M,Marchuk D,Wigler M,Collins FS,Ballester R

    更新日期:1993-03-01 00:00:00

  • Identification of expressed genes characterizing long-term survival in malignant glioma patients.

    abstract::Better understanding of the underlying biology of malignant gliomas is critical for the development of early detection strategies and new therapeutics. This study aimed to define genes associated with survival. We investigated whether genes coupled with a class prediction model could be used to define subgroups of hig...


    pub_type: 杂志文章


    authors: Yamanaka R,Arao T,Yajima N,Tsuchiya N,Homma J,Tanaka R,Sano M,Oide A,Sekijima M,Nishio K

    更新日期:2006-09-28 00:00:00

  • The E3 ubiquitin protein ligase MDM2 dictates all-trans retinoic acid-induced osteoblastic differentiation of osteosarcoma cells by modulating the degradation of RARα.

    abstract::Retinoic acid receptor alpha (RARα) has a critical role in the differentiation process of osteosarcoma cells induced by all-trans retinoic acid (ATRA). However, degradation of RARα through ubiquitin proteasome pathway weakens the differentiation efficiency of osteosarcoma cells. In this study, we discover that murine ...


    pub_type: 杂志文章


    authors: Ying M,Zhang L,Zhou Q,Shao X,Cao J,Zhang N,Li W,Zhu H,Yang B,He Q

    更新日期:2016-08-18 00:00:00

  • Neurotrophin-induced melanoma cell migration is mediated through the actin-bundling protein fascin.

    abstract::Expression of the p75 neurotrophin receptor (p75(NTR)) in primary melanomas is associated with deeply invasive lesions. In turn, there is expression of high levels of neurotrophins at the invasion front of normal tissue adjacent to brain metastases, thus implicating this growth factor-receptor system in melanoma tumor...


    pub_type: 杂志文章


    authors: Shonukan O,Bagayogo I,McCrea P,Chao M,Hempstead B

    更新日期:2003-06-05 00:00:00

  • Hyperphosphorylation of a novel 80 kDa protein-tyrosine kinase similar to Ltk in a human Ki-1 lymphoma cell line, AMS3.

    abstract::Ki-1 lymphoma is a subtype of human malignant lymphoma characterized by the expression of CD30 (Ki-1) and a peculiar morphology. It is occasionally accompanied by a unique reciprocal chromosomal translocation t(2;5)(p23;q35). A Ki-1 lymphoma cell line, AMS3, was established by maintaining biopsied tumor cells in SCID ...


    pub_type: 杂志文章


    authors: Shiota M,Fujimoto J,Semba T,Satoh H,Yamamoto T,Mori S

    更新日期:1994-06-01 00:00:00

  • Importin-β/karyopherin-β1 modulates mitotic microtubule function and taxane sensitivity in cancer cells via its nucleoporin-binding region.

    abstract::The nuclear transport receptor importin-β/karyopherin-β1 is overexpressed in cancers that display genomic instability. It is regarded as a promising cancer target and inhibitors are being developed. In addition to its role in nucleo-cytoplasmic transport, importin-β regulates mitosis, but the programmes and pathways i...


    pub_type: 杂志文章


    authors: Verrico A,Rovella P,Di Francesco L,Damizia M,Staid DS,Le Pera L,Schininà ME,Lavia P

    更新日期:2020-01-01 00:00:00