Antileukemic activity of Flt3 ligand in murine leukemia

Flt3-ligand (Flt3-L) is an early acting costimulatory cytokine that has bee n shown to possess antitumor properties in murine solid tumor models. Flt3- L is a hans-membrane protein (tm) but can be proteolytically cleaved to a s oluble form, which is also biologically active. In this study, the antitumo r effect of both soluble and tmFlt3-L was evaluated in a mouse leukemia mod el, To mimic the multiorgan involvement characteristic of human leukemia, a factor-dependent cell line FDC.91 was made leukemogenic by transfection wi th the human BCR/ABL gene. The resulting cell line, AW, expresses BCR/ABL R NA and protein. It maintains a similar in vitro growth rate as the parent c ell line,but unlike the parent cell Line, AW cells are factor independent a nd tumorigenic, Growth of FDC.P1 and AW cells are unaffected by the additio n of soluble human Flt3-L to the culture medium. Also, AW growth is unalter ed after transduction with a retroviral vector expressing the tm isoform of human Flt3-L (AW/tmFlt3-L), When 10(5) AW cells were i.v. injected into sy ngeneic DBA/2 mice, fatal leukemia developed in nine of nine (100%) mice wi thin 4-6 weeks with involvement of the blood, bone marrow, spleen, and thym us, Systematic administration of soluble human Flt3-L (500 mu g/kg/day) for 10 days protected mice from leukemia, with 11 of 17 mice tumor free at wee k 8 (64.7%) The hn isoform of Flt3-L also was protective. When 10(4) AW/tmF lt3-L cells were injected i.v. into mice, only 35.7% (5 of 14) developed le ukemia versus 100% in control groups. Adoptive transfer of immunity was als o demonstrated; T cells obtained from tumor-free animals conferred protecti on to 87% (seven of eight) naive mice challenged with AW cells. These resul ts demonstrate that both soluble and membrane-bound human Flt3-L has antitu mor activity in this leukemia model.