The myeloma-associated oncogene fibroblast growth factor receptor 3 is transforming in hematopoietic cells.
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.
Li
Z
Z
Departments of Medical Oncology and Pathology, The Princess Margaret Hospital, Toronto, Ontario, Canada.
Zhu
Y X
YX
Plowright
E E
EE
Bergsagel
P L
PL
Chesi
M
M
Patterson
B
B
Hawley
T S
TS
Hawley
R G
RG
Stewart
A K
AK
D000818:Animals; D016026:Bone Marrow Transplantation; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002999:Clone Cells / Q000473:pathology; D005260:Female; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D015322:Gene Rearrangement, B-Lymphocyte; D015329:Gene Rearrangement, T-Lymphocyte; D006412:Hematopoietic Stem Cells / Q000166:cytology*; D006801:Humans; D015851:Interleukin-7 / Q000494:pharmacology; D007964:Leukocytosis / Q000209:etiology / Q000235:genetics; D016393:Lymphoma, B-Cell / Q000209:etiology / Q000235:genetics; D008232:Lymphoproliferative Disorders / Q000209:etiology* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D009101:Multiple Myeloma / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D009857:Oncogenes; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000209:etiology / Q000235:genetics; D011505:Protein-Tyrosine Kinases; D011828:Radiation Chimera; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D013154:Spleen / Q000637:transplantation
D015851:Interleukin-7; D009363:Neoplasm Proteins; D017468:Receptors, Fibroblast Growth Factor; D011993:Recombinant Fusion Proteins; D005346:Fibroblast Growth Factors; C496365:FGFR3 protein, human; C496366:Fgfr3 protein, mouse; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3