Leukemic predisposition of mice transplanted with gene-modified hematopoietic precursors expressing flt3 ligand.
flt3/flk-2 ligand (FL) is a cytokine that exhibits synergistic activities in combination with other early acting factors on subpopulations of hematopoietic stem/progenitor cells. In addition to normal hematopoietic precursors, expression of the FL receptor, flt3R, has been frequently demonstrated on the blast cells from patients with acute B-lineage lymphoblastic, myeloid, and biphenotypic (also known as hybrid or mixed) 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 of the leukemic clone. In humans, FL is predominantly synthesized as a transmembrane protein that must undergo proteolytic cleavage to generate a soluble form. To investigate the consequences of constitutively expressing 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 transduced ex vivo with a recombinant retroviral vector (MSCV-FL) encoding murine transmembrane FL. Compared with control mice (8 total), MSCV-FL mice presented with a mild macrocytic anemia but were otherwise healthy for more than 5 months posttransplant (until 22 weeks). Subsequently, all primary MSCV-FL recipients observed for up to 1 year plus 83% (20 of 24) of secondary MSCV-FL animals that had received bone marrow from asymptomatic primary hosts reconstituted for 4 to 5 months developed transplantable hematologic malignancies (with mean latency periods of 30 and 23 weeks, respectively). Phenotypic and molecular analyses indicated 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+ precursors to leukemic transformation, underscore a potential role of this cytokine/receptor combination in certain human leukemias.
Hawley
T S
TS
Oncology Gene Therapy Program, The Toronto Hospital, and the Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada; the Institute of Pathology, University of Würzburg, Würzburg, Germany.
Fong
A Z
AZ
Griesser
H
H
Lyman
S D
SD
Hawley
R G
RG
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D002999:Clone Cells; D004198:Disease Susceptibility; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005822:Genetic Vectors / Q000235:genetics; D006410:Hematopoiesis / Q000235:genetics*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D007942:Leukemia, Experimental / Q000209:etiology / Q000235:genetics* / Q000473:pathology; D008024:Ligands; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D011994:Recombinant Proteins / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
D008024:Ligands; D008565:Membrane Proteins; D011994:Recombinant Proteins; C084881:flt3 ligand protein