Pim-1 levels determine the size of early B lymphoid compartments in bone marrow.

Abstract

SumnlaryThe mouse proto-oncogene Pim-1, which encodes two cytoplasmic serine-threonine-specific protein kinases, is frequently activated by proviral insertion in murine leukemia virus-induced hematopoietic tumors. Transgenic mice overexpressing Pim-1 show a low incidence of spontaneous T cell lymphomas, whereas null mutant mice lack an obvious phenotype. We have analyzed the early B lymphoid compartment from both null mutant and El~-Pim-1 transgenic mice. The level of Pim-1 expression appears to be a determining factor in the ability of these cells to respond to the growth factors interleukin 7 (IL-7) and SF (steel factor). The impaired response in null mutant mice could be rescued by introduction of a functional Pim-1 transgene. Moreover, overexpression of Pim-1 facilitates the derivation of primitive lymphoid cell lines that are dependent on combined stimulation with IL-7 and SF or insulin-like growth factor 1. These results for the first time identify the involvement of Pim-1 in a normal cellular function, as an important regulator of early B lymphopoiesis in mice.

Proviral activation of the tumor suppressor E2a contributes to T cell lymphomagenesis in EμMyc transgenic mice

“…Together with the notion that E2a is known to induce transcription of the immunoglobulin chains via binding to their regulatory E boxes (Murre et al, 1989;Bain et al, 1993;Shen and Kadesch, 1995) it however suggests that E2a insertions exert their oncogenic effect through altered expression of the transgene. This would be in line with our observation that proviral activations of E2a are early events in tumor initiation rather than tumor progression, and also explain the E2a insertion in the EmPim1 tumor, since it is known that the oncogenic potential of Pim1 is strongly dose-dependent (Domen et al, 1993;van der Lugt et al, 1995;Allen et al, 1997).…”

Reassessing the role of C-MYB in tumorigenesis

“…In vitro, there are defects in proliferative responses to IL-3 and IL-7 (Domen et al, 1993a,b,c). Conversely, analysis of Em-pim transgenics shows an enhancement in the size of IL-7-dependent early B cell compartments correlated with the degree of overexpression of the transgene (Domen et al, 1993a). This increase in immature cell number correlates with a loss of more mature cells, implying that overexpressing pim-1 may cause a dierentiation block.…”

Identification of the Autophosphorylation Sites of theXenopus laevis Pim-1 Proto-oncogene-encoded Protein Kinase

“…Expression and stability of pim-1 mRNA and protein is tightly regulated at different levels, implying that the kinase is functionally potent (7,9,(12)(13)(14). Pim-1 is induced by mitogens and growth factors, including GM-CSF, 1 G-CSF, IL-2, IL-3, IL-5, IL-6, IL-7, concanavalin A, phorbol esters, interferon-␥, Steel factor, and in response to T cell receptor cross-linking, and it may act as a cytoplasmic mediator in a signal transduction pathway (9,12,13,(15)(16)(17)(18). Up-regulation of Pim-1 by signaling through the GM-CSF receptor family requires the presence of the GM-CSF receptor membrane proximal domain and may involve the JAK2 tyrosine kinase (19 -24).…”