Retroviral transfer and expression of the interleukin-3 gene in hemopoietic cells.

Abstract

A recombinant retrovirus containing the interleukin-3 (IL3) coding sequence and the neomycin-resistance gene (Neo') has been generated. Infection of fetal liver cells with the IL3 retrovirus, but not with the N2 parental virus, resulted in the formation of factor-independent, Neo R colonies containing various types of differentiated hemopoietic cells. Established cell lines could be generated from these mixed hemopoietic colonies. These cell lines contained the unrearranged viral genome, produced viral IL3, and secreted the growth factor; however, they were not tumorigenic. Identical results were obtained from infection of two factor-dependent cell lines with the IL3 virus, except that these clones all became tumorigenic. These data indicate that endogenous IL3 production can support normal differentiation and immortalization of primary hemopoietic cells, or, in previously immortalized cells, can lead to tumorigenicity.

Retrovirus-mediated transfer and expression of the interleukin-3 gene in mouse hematopoietic cells result in a myeloproliferative disorder.

“…Introduction of the mouse gene for GM-CSF into a factor-dependent hematopoietic cell line (FDC-P1) resulted in autonomous growth and tumorgenicity (20). Analogous results have been obtained with the murine IL-3 gene (14,15,38). In some cases, autonomous growth appeared to depend on secretion of the growth factor (14,15,18), whereas cell proliferation of other growth factor-producing lines was insensitive to cell density and neutralizing antibody (6,20).…”

Aberrant Expression of the Multi-CSF Gene in Hematopoietic Precursor and Stem Cell Lines Initiates Leukemogenic Progression

“…Although initial reports suggested that aberrant factor expression leads directly to tumorigenic growth [6,8,9], the studies presented here and elsewhere [5,7,17] have clearly demonstrated that secondary events are necessary for true autonomous growth and increased tumorigenic potential. These secondary events may be dependent on the autogenous factor production or may have obtained selective advantage in cells producing their own factor.…”

“…Tumorigenesis of hemopoietic cells and acquisition of factor independence as a consequence of aberrant growth factor release are closely correlated [5][6][7][8][9]. In previous work we were able to dissect two stages leading to growth factor autonomy of cells: the first step requires the secretion of the constitutively expressed CSF gene product and extracellular interaction with its cognate receptor.…”

“…Several groups have shown that tumorigenicity may be a property of cells that have acquired factor-independent growth by autonomous CSF production [6][7][8][9]. Having dissected two stages of factor independence in vitro (density dependent versus autonomous growth), we investigated whether acquisition of either type of factor-independent growth was sufficient to induce tumor formation in susceptible mice or whether growth autonomy is prerequisite for tumorigenicity.…”

La coopération d'oncogènes dans la transformation cellulaire

“…Divers arguments en faveur de cette théorie ont été apportés par la génétique moléculaire (Duesberg, 1987 (Land et al, 1983). Un ré-sultat identique est obtenu lorsque l'oncogène ras est associé à l'oncogène N-myc (Yancopoulos et al, 1985), ou au protooncogène dérégulé c-jun (Schütte et al, 1989) Green, 1989;Weinberg, 1985 (Schwartz et al, 1986;Vaux et al, 1988 (Thompson et al, 1989 (Rüther et al, 1987(Rüther et al, , 1988 (Sinn et al, 1987 (Frykberg et al, 1983;Kahn et al, 1984;Johnson et al, 1989;Morishita et al, 1988;Carmier et Samarut, 1986;Lang et al, 1987;Wong et al, 1987;Neufeld et al, 1988 (Rosenthal et al, 1986;Stern et al, 1987;Jaye et al, 1988;Sasada et al, 1988;Rogelj et al, 1988 …”