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Blood, 15 April 2001, Vol. 97, No. 8, pp. 2413-2419
NEOPLASIA
The myeloma-associated oncogene fibroblast growth factor receptor
3 is transforming in hematopoietic cells
Zhihua Li,
Yuan Xiao Zhu,
Elizabeth E. Plowright,
P. Leif Bergsagel,
Marta Chesi,
Bruce Patterson,
Teresa S. Hawley,
Robert G. Hawley, and
A. Keith Stewart
From the Departments of Medical Oncology and Pathology,
The Princess Margaret Hospital, and The Toronto General Research
Institute, ON; Weill Medical College, Cornell University, New York, NY;
and Department of Hematopoiesis, Holland Laboratory, American Red
Cross, Rockville, MD.
Translocations involving fibroblast growth factor receptor 3 (fgfr3) have been identified in about 25% of patients with
myeloma. To directly examine the oncogenic potential of
fgfr3, murine bone marrow (BM) cells were transduced with
retroviral vectors containing either wild-type fgfr3 or an
activated mutant form of the receptor, fgfr3-TD. Mice
transplanted with FGFR3-TD-expressing BM developed a marked
leukocytosis and lethal hematopoietic cell infiltration of multiple
tissues within 6 weeks of transplantation. Secondary and tertiary
recipients of spleen or BM from primary fgfr3-TD mice also
developed tumors within 6 to 8 weeks. Analysis of the circulating tumor
cells revealed a pre-B-cell phenotype in most mice, although immature
T-lymphoid or mature myeloid populations also predominated in some
animals. Enhanced lymphoid but not myeloid colony formation was
observed in the early posttransplantation period and only interleukin 7 and FGF-responsive pre-B-cell lines could be established from tumors.
Cell expansions in primary recipients appeared polyclonal, whereas
tumors in later passages exhibited either clonal B- or T-cell receptor
gene rearrangements. Mice transplanted with wild-type FGFR3-expressing
BM developed delayed pro-B-cell lymphoma/leukemias approximately
1 year after transplantation. These studies confirm that FGFR3 is
transforming and can produce lymphoid malignancies in mice.
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