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Blood, Vol. 92 No. 6 (September 15), 1998:
pp. 2003-2011
Leukemic Predisposition of Mice Transplanted With Gene-Modified
Hematopoietic Precursors Expressing flt3 Ligand
Teresa S. Hawley,
Andrew Z.C. Fong,
Henrik Griesser,
Stewart D. Lyman, and
Robert G. Hawley
From the 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; and Immunex Corp, Seattle, WA.
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.
© 1998 by The American Society of Hematology.
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