Genetic fingerprinting of the development and progression of T-cell lymphoma in a murine model of atypical myeloproliferative disorder initiated by the ZNF198-fibroblast growth factor receptor-1 chimeric tyrosine kinase.
A mouse model of human ZNF198-fibroblast growth factor receptor-1 (FGFR1) stem cell leukemia lymphoma has been developed to investigate mechanisms of oncogenesis and progression. Using array-based comparative genomic hybridization, we followed disease progression after serial transplantation of ZNF198-FGFR1-transformed stem cells that give rise to a distinct myeloproliferative disorder and T-lymphoblastic leukemia. A consistent, frequently homozygous, chr14:53880459-55011545 deletion, containing the T-cell receptor alpha and delta genes, was identified in the bone marrow, spleen, and lymph nodes in all cases. The absence of cell-surface T-cell receptor alpha in tumor cells precludes CD3 recruitment, resulting in loss of a functional T-cell receptor complex, supporting the idea that prevention of maturation of CD4(+)/CD8(+) double-positive immature T cells is important in ZNF198-FGFR1 disease development. Up-regulation of the B-cell line 2, interleukin 7 receptor alpha and interleuking 2 receptor alpha prosurvival genes in these undifferentiated tumor precursor cells suggests one mechanism that allows them to escape apoptosis in the thymus. Thus, we have defined an important event in the process of ZNF198-FGFR1-induced T-cell leukemia.
Ren
Mingqiang
M
Medical College of Georgia Cancer Center, Augusta, GA 30912, USA.
Li
Xiurong
X
Cowell
John K
JK
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002478:Cells, Cultured; D055028:Comparative Genomic Hybridization; D016172:DNA Fingerprinting; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006412:Hematopoietic Stem Cells / Q000473:pathology; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008954:Models, Biological; D009196:Myeloproliferative Disorders / Q000235:genetics* / Q000473:pathology; D009368:Neoplasm Transplantation / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000473:pathology / Q000637:transplantation; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C498438:Zmym2 protein, mouse; D051496:Receptor, Fibroblast Growth Factor, Type 1