title: Pim1 and Myc reversibly transform murine precursor B lymphocytes but not mature B lymphocytes.
abstract: The proto-oncogenes Myc and Pim1, which are deregulated in many types of cancers, are known to cooperate in B lymphoma development. Here we show that overexpression of retrovirally transduced, doxycycline-inducible Myc alone in IL-7-deprived, growth-arrested pre-B cells enhanced cell cycle entry without impairing apoptosis. Overexpression of Pim1 decreased apoptosis, but had no effect on cell cycle entry. Co-expression of Pim1 and Myc inhibited apoptosis and led to IL-7-independent proliferation of the transduced pre-B cells in vitro, while blocking their differentiation to IgM(+)  immature cells. Transplantation of Pim1/Myc overexpressing pre-BI cells into B-cell-deficient mice expanded the pre-B-cell compartments up to 100-fold within 4-8 weeks. Transformation remained dependent on the expression of both oncogenes, as removal of doxycycline in vitro and in vivo terminated proliferation and induced differentiation to IgM(+)  B cells. In contrast, Pim1/Myc-transduced mature B cells that developed from the oncogene-transduced pre-BI cells in the absence of oncogene overexpression in vivo were not capable of long-term proliferation after induction of Pim and Myc overexpression, neither in vivo nor in vitro, neither with nor without stimulation by polyclonal activators.
authors.affiliation: Department of Lymphocyte Development, MPI for Infection Biology, Berlin, Germany.
authors.forename: Corinne
authors.initials: C
authors.lastname: Bouquet
authors.forename: Fritz
authors.initials: F
authors.lastname: Melchers
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D002453:Cell Cycle / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D048708:Cell Growth Processes / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D002472:Cell Transformation, Viral; D017690:Cell Transplantation; D004318:Doxycycline / Q000008:administration & dosage; D005822:Genetic Vectors / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D015851:Interleukin-7 / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054448:Precursor Cells, B-Lymphoid / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051573:Proto-Oncogene Proteins c-pim-1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D012190:Retroviridae / Q000235:genetics*; D019076:Transgenes / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; D015851:Interleukin-7; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; C064658:RAG-1 protein; D051573:Proto-Oncogene Proteins c-pim-1; D004318:Doxycycline