LEUKEMIC PREDISPOSITION OF MICE TRANSPLANTED WITH GENE-MODIFIED HEMATOPOIETIC PRECURSORS EXPRESSING FLT3 LIGAND

flt3/fIk-2 ligand (FL) is a cytokine that exhibits synergistic activit ies in combination with other early acting factors on subpopulations o f hematopoietic stem/progenitor cells. In addition to normal hematopoi etic precursors, expression of the FL receptor, flt3R, has been freque ntly demonstrated on the blast cells from patients with acute B-lineag e lymphoblastic, myeloid, and biphenotypic (also known as hybrid or mi xed) leukemias. Because many of these leukemic cell types express FL, the possibility has been raised that altered regulation of FL-mediated signaling might contribute to malignant transformation or expansion o f the leukemic clone. In humans, FL is predominantly synthesized as a transmembrane protein that must undergo proteolytic cleavage to genera te a soluble form. To investigate the consequences of constitutively e xpressing the analogous murine FL isoform in murine hematopoietic stem /progenitor cells, lethally irradiated syngeneic mice (18 total) were engrafted with post-5-fluorouracil-treated bone marrow cells transduce d ex vivo with a recombinant retroviral vector (MSC-VFL) encoding muri ne transmembrane FL. Compared with control mice (8 total), MSCV-FL mic e presented with a mild macrocytic anemia but were otherwise healthy f or more than 5 months posttransplant (until 22 weeks). Subsequently, a ll primary MSCV-FL recipients observed for up to 1 year plus 83% (20 o f 24) of secondary MSCV-FL animals that had received bone marrow from asymptomatic primary hosts reconstituted for 4 to 5 months developed t ransplantable hematologic malignancies (with mean latency periods of 3 0 and 23 weeks, respectively). Phenotypic and molecular analyses indic ated that the tumor cells expressed flt3R and displayed B-cell and/or myeloid markers. These data, establishing that dysregulated expression of FL in primitive hematopoietic cells predisposes flt3R(+) precursor s to leukemic transformation, underscore a potential role of this cyto kine/ receptor combination in certain human leukemias. (C) 1998 by The American Society of Hematology.