Malignant transformation of early lymphoid progenitors in mice expressing an activated Blk tyrosine kinase.

The intracellular signals governing cellular proliferation and developmental progression during lymphocyte development are incompletely understood. The tyrosine kinase Blk is expressed preferentially in the B lineage, but its function in B cell development has been largely unexplored. We have generated transgenic mice expressing constitutively active Blk [Blk(Y495F)] in the B and T lymphoid compartments. Expression of Blk(Y495F) in the B lineage at levels similar to that of endogenous Blk induced B lymphoid tumors of limited clonality, whose phenotypes are characteristic of B cell progenitors at the proB/preB-I to preB-II transition. Expression of constitutively active Blk in the T lineage resulted in the appearance of clonal, thymic lymphomas composed of intermediate single positive cells. Taken together, these results indicate that specific B and T cell progenitor subsets are preferentially susceptible to transformation by Blk(Y495F) and suggest a role for Blk in the control of proliferation during B cell development.

[1]  Philippe Soriano,et al.  Knockouts of Src-family kinases: stiff bones, wimpy T cells, and bad memories. , 1996, Genes & development.

[2]  F. Alt,et al.  Function of the pre-T-cell receptor alpha chain in T-cell development and allelic exclusion at the T-cell receptor beta locus. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[3]  T. Yamamoto,et al.  Impaired proliferation of peripheral B cells and indication of autoimmune disease in lyn-deficient mice. , 1995, Immunity.

[4]  S. Stacker,et al.  Multiple defects in the immune system of Lyn-deficient mice, culminating in autoimmune disease , 1995, Cell.

[5]  M.,et al.  Involvement of p59fynT in interleukin-5 receptor signaling [published erratum appears in J Exp Med 1995 Oct 1;182(4):1179] , 1995, The Journal of experimental medicine.

[6]  R. Hardy,et al.  Differential expression of the blk and ret tyrosine kinases during B lineage development is dependent on Ig rearrangement. , 1995, Journal of immunology.

[7]  H. Fehling,et al.  Crucial role of the pre-T-cell receptor α gene in development of ap but not γδ T cells , 1995, Nature.

[8]  S. Desiderio,et al.  V(D)J recombination and the cell cycle. , 1995, Immunology today.

[9]  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.

[10]  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.

[11]  J. Fargnoli,et al.  Temporal regulation of non-transmembrane protein tyrosine kinase enzyme activity following T cell antigen receptor engagement. , 1994, The Journal of biological chemistry.

[12]  T. Winkler,et al.  IL-2 receptor α chain (CD25JAC) expression defines a crucial stage in pre-B cell development , 1994 .

[13]  S. Tonegawa,et al.  Onset of TCR-beta gene rearrangement and role of TCR-beta expression during CD3-CD4-CD8- thymocyte differentiation. , 1994, Journal of immunology.

[14]  D. Baltimore,et al.  Functional immunoglobulin transgenes guide ordered B-cell differentiation in Rag-1-deficient mice. , 1994, Genes & development.

[15]  F. Alt,et al.  The expression of Vpre-B/λ5 surrogate light chain in early bone marrow precursor B cells of normal and B cell-deficient mutant mice , 1994, Cell.

[16]  K. Rajewsky,et al.  Early B‐Cell Development in the Mouse: Insights from Mutations Introduced by Gene Targeting , 1994, Immunological reviews.

[17]  M. Groettrup,et al.  A role for a pre-T-cell receptor in T-cell development. , 1993, Immunology today.

[18]  A. Zlotnik,et al.  Control points in early T-cell development. , 1993, Immunology today.

[19]  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.

[20]  R. Perlmutter,et al.  A dominant‐negative transgene defines a role for p56lck in thymopoiesis. , 1993, The EMBO journal.

[21]  F. Alt,et al.  Restoration of T cell development in RAG-2-deficient mice by functional TCR transgenes. , 1993, Science.

[22]  A. Rolink,et al.  Surrogate light chain in B cell development. , 1993, Advances in immunology.

[23]  M. Berridge.  Inositol trisphosphate and calcium signalling , 1993, Nature.

[24]  K. M. Abraham,et al.  Inhibition of T‐cell receptor beta‐chain gene rearrangement by overexpression of the non‐receptor protein tyrosine kinase p56lck. , 1992, The EMBO journal.

[25]  T. Rabbitts,et al.  T-cell acute lymphoblastic lymphoma induced in transgenic mice by the RBTN1 and RBTN2 LIM-domain genes. , 1992, Oncogene.

[26]  G. Sclar,et al.  Thymic overexpression of Ttg-1 in transgenic mice results in T-cell acute lymphoblastic leukemia/lymphoma , 1992, Molecular and cellular biology.

[27]  A. Wakeham,et al.  Profound block in thymocyte development in mice lacking p56lck , 1992, Nature.

[28]  S. Winistorfer,et al.  Recombinant circle PCR and recombination PCR for site-specific mutagenesis without PCR product purification. , 1992, BioTechniques.

[29]  K. Zeller,et al.  Structure and developmental regulation of the B-lymphoid tyrosine kinase gene blk. , 1992, The Journal of biological chemistry.

[30]  K. M. Abraham,et al.  Thymic tumorigenesis induced by overexpression of p56lck. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[31]  J D Kemp,et al.  Resolution and characterization of pro-B and pre-pro-B cell stages in normal mouse bone marrow , 1991, The Journal of experimental medicine.

[32]  D. Baltimore,et al.  Virus-transformed pre-B cells show ordered activation but not inactivation of immunoglobulin gene rearrangement and transcription , 1991, The Journal of experimental medicine.

[33]  R. Sen,et al.  Multiple nuclear factors interact with sequences within the J beta 2-C beta 2 intron of the murine T cell receptor beta-chain gene. , 1990, Journal of immunology.

[34]  H. Pircher,et al.  T cell tolerance to Mlsa encoded antigens in T cell receptor V beta 8.1 chain transgenic mice. , 1989, The EMBO journal.

[35]  H. Macdonald,et al.  A cd3− subset of cd4−8+ thymocytes: a rapidly cycling intermediate in the generation of cd4+8+ cells , 1988, European journal of immunology.

[36]  F. Alt,et al.  Continuing kappa-gene rearrangement in a cell line transformed by Abelson murine leukemia virus , 1982, Cell.