Ectopic expression of B-lymphoid kinase in cutaneous T-cell lymphoma.

B-lymphoid kinase (Blk) is exclusively expressed in B cells and thymocytes. Interestingly, transgenic expression of a constitutively active form of Blk in the T-cell lineage of mice results in the development of T-lymphoid lymphomas. Here, we demonstrate nuclear factor-kappa B (NF-kappaB)-mediated ectopic expression of Blk in malignant T-cell lines established from patients with cutaneous T-cell lymphoma (CTCL). Importantly, Blk is also expressed in situ in lesional tissue specimens from 26 of 31 patients with CTCL. Already in early disease the majority of epidermotropic T cells express Blk, whereas Blk expression is not observed in patients with benign inflammatory skin disorders. In a longitudinal study of an additional 24 patients biopsied for suspected CTCL, Blk expression significantly correlated with a subsequently confirmed diagnosis of CTCL. Blk is constitutively tyrosine phosphorylated in malignant CTCL cell lines and spontaneously active in kinase assays. Furthermore, targeting Blk activity and expression by Src kinase inhibitors and small interfering RNA (siRNA) inhibit the proliferation of the malignant T cells. In conclusion, this is the first report of Blk expression in CTCL, thereby providing new clues to the pathogenesis of the disease.

[1]  C. Geisler,et al.  Malignant Tregs express low molecular splice forms of FOXP3 in Sézary syndrome , 2008, Leukemia.

[2]  C. Paweletz,et al.  Constitutive activation of signal transducers and activators of transcription predicts vorinostat resistance in cutaneous T-cell lymphoma. , 2008, Cancer research.

[3]  G. Courtois,et al.  Inhibition of IκB Kinase Subunit 2 in Cutaneous T-Cell Lymphoma Down-Regulates Nuclear Factor-κB Constitutive Activation, Induces Cell Death, and Potentiates the Apoptotic Response to Antineoplastic Chemotherapeutic Agents , 2008, Clinical Cancer Research.

[4]  A. Hauschild,et al.  Maintenance therapy in cutaneous T-cell lymphoma: who, when, what? , 2007, European journal of cancer.

[5]  C. Geisler,et al.  Nonmalignant T cells stimulate growth of T-cell lymphoma cells in the presence of bacterial toxins. , 2007, Blood.

[6]  L. F. Glass,et al.  The diagnosis, staging, and treatment options for mycosis fungoides. , 2007, Cancer control : journal of the Moffitt Cancer Center.

[7]  J. Becker,et al.  Jak3- and JNK-dependent vascular endothelial growth factor expression in cutaneous T-cell lymphoma , 2006, Leukemia.

[8]  M. Wasik,et al.  STAT3 induces transcription of the DNA methyltransferase 1 gene (DNMT1) in malignant T lymphocytes. , 2006, Blood.

[9]  R. Dummer,et al.  EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome. , 2006, European journal of cancer.

[10]  G. Courtois,et al.  Down-regulating constitutive activation of the NF-kappaB canonical pathway overcomes the resistance of cutaneous T-cell lymphoma to apoptosis. , 2006, Blood.

[11]  S. Klinken,et al.  Cross-regulation of JAK and Src kinases , 2006, Growth factors.

[12]  Nicola Pimpinelli,et al.  Defining early mycosis fungoides. , 2005, Journal of the American Academy of Dermatology.

[13]  C. Geisler,et al.  Increased sensitivity to interferon-α in psoriatic T cells , 2005 .

[14]  Nicola Pimpinelli,et al.  WHO-EORTC classification for cutaneous lymphomas. , 2005, Blood.

[15]  E. Bettelli,et al.  Foxp3 interacts with nuclear factor of activated T cells and NF-kappa B to repress cytokine gene expression and effector functions of T helper cells. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[16]  L. Showe,et al.  Immunopathogenesis and therapy of cutaneous T cell lymphoma. , 2005, The Journal of clinical investigation.

[17]  M. Wasik,et al.  In vivo activation of STAT3 in cutaneous T-cell lymphoma. Evidence for an antiapoptotic function of STAT3 , 2004, Leukemia.

[18]  L. Wilson,et al.  The pathogenesis of mycosis fungoides. , 2004, The New England journal of medicine.

[19]  S. Dehm,et al.  SRC gene expression in human cancer: the role of transcriptional activation. , 2004, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[20]  S. Desiderio,et al.  Mimicry of Pre–B Cell Receptor Signaling by Activation of the Tyrosine Kinase Blk , 2003, The Journal of experimental medicine.

[21]  G. Gallick,et al.  Src family kinases in tumor progression and metastasis , 2003, Cancer and Metastasis Reviews.

[22]  E. Glusac.  Criterion by criterion, mycosis fungoides. , 2003, The American Journal of dermatopathology.

[23]  A. Tarakhovsky,et al.  Essential role of Src-family protein tyrosine kinases in NF-κB activation during B cell development , 2003, Nature Immunology.

[24]  L. Ellis,et al.  Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis , 2002, Oncogene.

[25]  R. Edelson.  Cutaneous T Cell Lymphoma , 2001, The Journal of dermatologic surgery and oncology.

[26]  S. Alkan,et al.  Constitutive expression of NF-kappa B is a characteristic feature of mycosis fungoides: implications for apoptosis resistance and pathogenesis. , 2000, Human pathology.

[27]  T. Mustelin,et al.  Lck is involved in interleukin-2 induced proliferation but not cell survival in human T cells through a MAP kinase-independent pathway. , 2000, European cytokine network.

[28]  C. Geisler,et al.  Inhibition of constitutively activated Stat3 correlates with altered Bcl-2/Bax expression and induction of apoptosis in mycosis fungoides tumor cells , 1999, Leukemia.

[29]  P. Zwollo,et al.  The Transcription Factor NF-κB/p50 Interacts with the blkGene during B Cell Activation* , 1998, The Journal of Biological Chemistry.

[30]  H. Dintzis,et al.  Malignant transformation of early lymphoid progenitors in mice expressing an activated Blk tyrosine kinase. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[31]  R. Halaban,et al.  Diminished TCR signaling in cutaneous T cell lymphoma is associated with decreased activities of Zap70, Syk and membrane-associated Csk , 1997, Leukemia.

[32]  D. Seldin,et al.  Analysis of IL-2, IL-4 and their receptors in clonally-related cell lines derived from a patient with a progressive cutaneous T-cell lymphoproliferative disorder. , 1996, Leukemia & lymphoma.

[33]  C. B. Pedersen,et al.  Common clonal chromosome aberrations in cytokine-dependent continuous human T-lymphocyte cell lines. , 1995, Cancer genetics and cytogenetics.

[34]  M. Campbell,et al.  Transcription of the blk Gene in Human B Lymphocytes Is Controlled by Two Promoters (*) , 1995, The Journal of Biological Chemistry.

[35]  C. Baldari,et al.  p56lck plays a key role in transducing apoptotic signals in T cells , 1995, FEBS letters.

[36]  J. Niederhuber,et al.  Molecular cloning and chromosomal localization of the human homologue of a B-lymphocyte specific protein tyrosine kinase (blk). , 1995, Oncogene.

[37]  C. I. Smith,et al.  Molecular cloning, characterization, and chromosomal localization of a human lymphoid tyrosine kinase related to murine Blk. , 1995, Journal of immunology.

[38]  H. Hanafusa,et al.  Functional analysis of Csk in signal transduction through the B-cell antigen receptor , 1994, Molecular and cellular biology.

[39]  J. Fargnoli,et al.  Temporal differences in the activation of three classes of non-transmembrane protein tyrosine kinases following B-cell antigen receptor surface engagement. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[40]  S. Desiderio,et al.  Specific recognition of the blk promoter by the B-lymphoid transcription factor B-cell-specific activator protein. , 1994, The Journal of biological chemistry.

[41]  K. thestrup-pedersen,et al.  Cytogenetic findings in cell lines from cutaneous T-cell lymphoma. , 1994, Dermatologic clinics.

[42]  S. Malek,et al.  SH2 domains of the protein-tyrosine kinases Blk, Lyn, and Fyn(T) bind distinct sets of phosphoproteins from B lymphocytes. , 1993, The Journal of biological chemistry.

[43]  Philippe Soriano,et al.  Disruption of the csk gene, encoding a negative regulator of Src family tyrosine kinases, leads to neural tube defects and embryonic lethality in mice , 1993, Cell.

[44]  E. Boel,et al.  Establishment of two continuous T-cell strains from a single plaque of a patient with mycosis fungoides , 1992, In Vitro Cellular & Developmental Biology - Animal.

[45]  A. Burkhardt,et al.  Anti-immunoglobulin stimulation of B lymphocytes activates src-related protein-tyrosine kinases. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[46]  A. Weiss,et al.  Association of the human CD3-zeta chain with the alpha beta-T cell receptor/CD3 complex. Clues from a T cell variant with a mutated T cell receptor-alpha chain. , 1990, Journal of immunology.

[47]  J. Siegel,et al.  A bioassay for the measurement of human interleukin-4. , 1990, Journal of immunological methods.

[48]  S. Desiderio,et al.  Specific expression of a tyrosine kinase gene, blk, in B lymphoid cells. , 1990, Science.

[49]  B. Thiers.  Revisions to the staging and classification of mycosis fungoides and Sézary syndrome: a proposal of the International Society for Cutaneous Lymphomas (ISCL) and the cutaneous lymphoma task force of the European Organization of Research and Treatment of Cancer (EORTC) , 2008 .

[50]  C. Geisler,et al.  Increased sensitivity to interferon-alpha in psoriatic T cells. , 2005, The Journal of investigative dermatology.

[51]  R. Edelson.  Cutaneous T cell lymphoma: the helping hand of dendritic cells. , 2001, Annals of the New York Academy of Sciences.

[52]  P. Zwollo,et al.  The transcription factor NF-kappaB/p50 interacts with the blk gene during B cell activation. , 1998, The Journal of biological chemistry.

[53]  Sheila M. Thomas,et al.  Cellular functions regulated by Src family kinases. , 1997, Annual review of cell and developmental biology.