The A-Myb transcription factor is a marker of centroblasts in vivo.

The A-Myb transcription factor is structurally related to the c-myb proto-oncogene and is involved in the control of proliferation and/or differentiation of mature B lymphocytes. We have shown previously by PCR analysis that A-myb is preferentially expressed in CD38+ CD39- sIgM- mature B cells. We demonstrate here, using in situ hybridization, that A-myb expression is restricted to the dark zone of human tonsils and lymph nodes. Furthermore, we show that A-Myb expression is cell cycle regulated both in tonsillar B cells and in Burkitt's lymphoma cell lines, being detectable only in the S and G2/M phases of the cell cycle and not in G0/G1 phase. Strong proliferation of resting human B cells induced in vitro by a variety of physiologic signals, including anti-mu, CD40 ligand, IL-2, IL-4, IL-6, IL-13, IFN-gamma, TNF-alpha, anti-CD19, and anti-CD20, failed to induce A-myb expression, suggesting that proliferation alone is not sufficient for A-myb expression in the absence of induction of a true centroblast phenotype. Finally, we show that differentiation of germinal center B cells in vitro toward either memory or plasma cells is accompanied by rapid down-regulation of A-myb expression. We conclude that A-myb is a marker of centroblasts generated in vivo.

[1]  J. Banchereau,et al.  Interleukin-10 induces immunoglobulin G isotype switch recombination in human CD40-activated naive B lymphocytes , 1996, The Journal of experimental medicine.

[2]  V. Facchinetti,et al.  The A-myb transcription factor in neoplastic and normal B cells. , 1997, Leukemia & lymphoma.

[3]  E. Reddy,et al.  Temporal patterns of A-myb and B-myb gene expression during testis development. , 1996, Oncogene.

[4]  N. Copeland,et al.  Mouse A‐myb encodes a trans‐activator and is expressed in mitotically active cells of the developing central nervous system, adult testis and B lymphocytes. , 1994, The EMBO journal.

[5]  Johannes Gerdes,et al.  Production of a mouse monoclonal antibody reactive with a human nuclear antigen associated with cell proliferation , 1983, International journal of cancer.

[6]  S. Swerdlow,et al.  A functional c-myb gene is required for normal murine fetal hepatic hematopoiesis , 1991, Cell.

[7]  T. Graf,et al.  Ts mutants of E26 leukemia virus allow transformed myeloblasts, but not erythroblasts or fibroblasts to differentiate at the nonpermissive temperature , 1984, Cell.

[8]  A. Levinson,et al.  The product of the retroviral transforming gene v-myb is a truncated version of the protein encoded by the cellular oncogene c-myb , 1983, Cell.

[9]  S. Songia,et al.  Regulation of hematopoietic cell proliferation and differentiation by themyb oncogene family of transcription factors , 1996, International journal of clinical & laboratory research.

[10]  M. Klemsz,et al.  Transmembrane Signals and Intracellular “Second Messengers” in the Regulation of Quiescent B‐Lymphocyte Activation , 1987, Immunological reviews.

[11]  Mark M. Davis,et al.  Blimp-1, a novel zinc finger-containing protein that can drive the maturation of B lymphocytes into immunoglobulin-secreting cells , 1994, Cell.

[12]  D. Liebermann,et al.  Deregulated c-myb disrupts interleukin-6- or leukemia inhibitory factor-induced myeloid differentiation prior to c-myc: role in leukemogenesis , 1992, Molecular and cellular biology.

[13]  W. Kuehl,et al.  Differentiation of mouse erythroleukemia cells is blocked by late up-regulation of a c-myb transgene , 1990, Molecular and cellular biology.

[14]  A. Mantovani,et al.  B-myb antisense oligonucleotides inhibit proliferation of human hematopoietic cell lines. , 1992, Blood.

[15]  A. Mantovani,et al.  Characterization of the new immunosuppressive drug undecylprodigiosin in human lymphocytes: retinoblastoma protein, cyclin-dependent kinase-2, and cyclin-dependent kinase-4 as molecular targets. , 1997, Journal of immunology.

[16]  A. Toscani,et al.  Arrest of spermatogenesis and defective breast development in mice lacking A-myb , 1997, Nature.

[17]  B. Calabretta,et al.  Growth regulated expression of B‐MYB in fibroblasts and hematopoietic cells , 1991, Journal of cellular physiology.

[18]  I. Maclennan,et al.  Quantitative analysis of molecules which distinguish functional compartments within germinal centers , 1993, European journal of immunology.

[19]  B. Calabretta,et al.  Ectopic expression of A-myb in transgenic mice causes follicular hyperplasia and enhanced B lymphocyte proliferation. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[20]  K. Rajewsky,et al.  Tracing B cell development in human germinal centres by molecular analysis of single cells picked from histological sections. , 1993, The EMBO journal.

[21]  M. Arsura,et al.  Expression of c-myb and B-myb, but not A-myb, correlates with proliferation in human hematopoietic cells , 1991 .

[22]  M. Arsura,et al.  Dissociation between p93B-myb and p75c-myb expression during the proliferation and differentiation of human myeloid cell lines. , 1994, Blood.

[23]  J. Banchereau,et al.  Within germinal centers, isotype switching of immunoglobulin genes occurs after the onset of somatic mutation. , 1996, Immunity.

[24]  J. Banchereau,et al.  CD40 and B cell antigen receptor dual triggering of resting B lymphocytes turns on a partial germinal center phenotype , 1996, The Journal of experimental medicine.

[25]  M. Arsura,et al.  A-myb is expressed in bovine vascular smooth muscle cells during the late G1-to-S phase transition and cooperates with c-myc to mediate progression to S phase , 1997, Molecular and cellular biology.

[26]  R. Noelle,et al.  CD40 and its ligand. , 1996, Advances in immunology.

[27]  W. Strober,et al.  BSAP: a key regulator of B-cell development and differentiation. , 1995, Immunology today.

[28]  M. Castellano,et al.  The human A-myb protein is a strong activator of transcription. , 1994, Oncogene.

[29]  M. Arsura,et al.  The DNA Binding Domain of the A-MYB Transcription Factor Is Responsible for Its B Cell-specific Activity and Binds to a B Cell 110-kDa Nuclear Protein* , 1997, The Journal of Biological Chemistry.

[30]  M. Arsura,et al.  The myb oncogene family of transcription factors: potent regulators of hematopoietic cell proliferation and differentiation. , 1994, Seminars in cancer biology.

[31]  C. Hovens,et al.  A B-cell coactivator of octamer-binding transcription factors , 1995, Nature.

[32]  M. Fiscella,et al.  Constitutive expression of B-myb can bypass p53-induced Waf1/Cip1-mediated G1 arrest. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[33]  T. Barbui,et al.  Expression of A-myb, but not c-myb and B-myb, is restricted to Burkitt's lymphoma, sIg+ B-acute lymphoblastic leukemia, and a subset of chronic lymphocytic leukemias , 1996 .

[34]  A. Toscani,et al.  Murine A-myb: evidence for differential splicing and tissue-specific expression. , 1994, Oncogene.

[35]  J. Banchereau,et al.  Generation of memory B cells and plasma cells in vitro , 1995, Science.

[36]  S. Bernasconi,et al.  The A-myb gene is preferentially expressed in tonsillar CD38+, CD39-, and sIgM- B lymphocytes and in Burkitt's lymphoma cell lines. , 1994, Journal of immunology.

[37]  M. Ferrarini,et al.  B cells and their fate in health and disease. , 1996, Immunology today.

[38]  B. Calabretta,et al.  A c-myb antisense oligodeoxynucleotide inhibits normal human hematopoiesis in vitro. , 1988, Science.

[39]  N. Nomura,et al.  Isolation of human cDNA clones of myb-related genes, A-myb and B-myb. , 1988, Nucleic acids research.

[40]  M. Lipinski,et al.  Identification of a subset of normal B cells with a Burkitt's lymphoma (BL)-like phenotype. , 1987, Journal of immunology.

[41]  Y. S. Choi,et al.  Cellular and molecular factors that regulate the differentiation and apoptosis of germinal center B cells. Anti-Ig down-regulates Fas expression of CD40 ligand-stimulated germinal center B cells and inhibits Fas-mediated apoptosis. , 1996, Journal of immunology.

[42]  I. Herskowitz,et al.  Joining the complex: Cyclin-dependent kinase inhibitory proteins and the cell cycle , 1994, Cell.

[43]  T. Graf,et al.  v‐Myb DNA binding is required to block thrombocytic differentiation of Myb‐Ets‐transformed multipotent haematopoietic progenitors. , 1995, The EMBO journal.

[44]  G. Kelsoe.  Life and death in germinal centers (redux). , 1996, Immunity.

[45]  M. Groudine,et al.  Expression of the c-myb proto-oncogene during cellular proliferation , 1986, Nature.

[46]  K. Offit,et al.  BCL-6 protein is expressed in germinal-center B cells. , 1995, Blood.