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Acute progression of BCR-FGFR1 induced murine B-lympho/myeloproliferative disorder suggests involvement of lineages at the pro-B cell stage.

Ren M, Tidwell JA, Sharma S, Cowell JK - PLoS ONE (2012)

Bottom Line: Constitutive activation of FGFR1, through rearrangement with various dimerization domains, leads to atypical myeloproliferative disorders where, although T cell lymphoma are common, the BCR-FGFR1 chimeric kinase results in CML-like leukemia.The B220(-) phenotype was retained in one of the cell lines while the other was B220(+).When the two cell lines were transplanted into syngeneic mice, all animals developed the same B-lymphoblastic leukemia within 2-weeks.

View Article: PubMed Central - PubMed

Affiliation: Georgia Health Sciences University Cancer Center, Georgia Health Sciences University School of Medicine, Augusta, Georgia, United States of America.

ABSTRACT
Constitutive activation of FGFR1, through rearrangement with various dimerization domains, leads to atypical myeloproliferative disorders where, although T cell lymphoma are common, the BCR-FGFR1 chimeric kinase results in CML-like leukemia. As with the human disease, mouse bone marrow transduction/transplantation with BCR-FGFR1 leads to CML-like myeloproliferation as well as B-cell leukemia/lymphoma. The murine disease described in this report is virtually identical to the human disease in that both showed bi-lineage involvement of myeloid and B-cells, splenomegaly, leukocytosis and bone marrow hypercellularity. A CD19(+) IgM(-) CD43(+) immunophenotype was seen both in primary tumors and two cell lines derived from these tumors. In all primary tumors, subpopulations of these CD19(+) IgM(-) CD43(+) were also either B220(+) or B220(-), suggesting a block in differentiation at the pro-B cell stage. The B220(-) phenotype was retained in one of the cell lines while the other was B220(+). When the two cell lines were transplanted into syngeneic mice, all animals developed the same B-lymphoblastic leukemia within 2-weeks. Thus, the murine model described here closely mimics the human disease with bilineage myeloid and B-cell leukemia/lymphoma which provides a representative model to investigate therapeutic intervention and a better understanding of the etiology of the disease.

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B-cell leukemia/lymphoma induced by BCR-FGFR1 is transplantable.A) Kaplan-Meier survival analysis of the second generation of BCR-FGFR1 mice, which were transplanted with BM cells (0.6–1.5×106 cell per mouse) from lethally irradiated primary recipients. B) Representative flow analysis shows that lymphoma/tumor cells from a second serial transplanted mouse are differentially blocked at the pro-B stage.
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pone-0038265-g003: B-cell leukemia/lymphoma induced by BCR-FGFR1 is transplantable.A) Kaplan-Meier survival analysis of the second generation of BCR-FGFR1 mice, which were transplanted with BM cells (0.6–1.5×106 cell per mouse) from lethally irradiated primary recipients. B) Representative flow analysis shows that lymphoma/tumor cells from a second serial transplanted mouse are differentially blocked at the pro-B stage.

Mentions: To determine transplantability of these lymphomas, BM cells from the 5 lethally irradiated mice were each transplanted into 3–5 secondary recipients that had been sublethally irradiated (600 Gy). Depending on the number of cells obtained from the primary transplanted mice, 0.6–1.5×106 cells were transplanted and leukemias developed within 2–10 weeks suggesting fully transformed leukemic stem cells were present in the BM. The latency period in the secondary transplanted mice was similar to that seen in the primary recipients and the median survival time was ∼ 30 days (Figure 3A). The immunophenotype of the secondary transplanted mice was also similar to that in the primary mice (Figure 3B). Because all secondary transplanted mice simultaneously developed transplantable myeloid and B-lineage disease suggests that the disease initiates from progenitor cells or stem cells.


Acute progression of BCR-FGFR1 induced murine B-lympho/myeloproliferative disorder suggests involvement of lineages at the pro-B cell stage.

Ren M, Tidwell JA, Sharma S, Cowell JK - PLoS ONE (2012)

B-cell leukemia/lymphoma induced by BCR-FGFR1 is transplantable.A) Kaplan-Meier survival analysis of the second generation of BCR-FGFR1 mice, which were transplanted with BM cells (0.6–1.5×106 cell per mouse) from lethally irradiated primary recipients. B) Representative flow analysis shows that lymphoma/tumor cells from a second serial transplanted mouse are differentially blocked at the pro-B stage.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3368885&req=5

pone-0038265-g003: B-cell leukemia/lymphoma induced by BCR-FGFR1 is transplantable.A) Kaplan-Meier survival analysis of the second generation of BCR-FGFR1 mice, which were transplanted with BM cells (0.6–1.5×106 cell per mouse) from lethally irradiated primary recipients. B) Representative flow analysis shows that lymphoma/tumor cells from a second serial transplanted mouse are differentially blocked at the pro-B stage.
Mentions: To determine transplantability of these lymphomas, BM cells from the 5 lethally irradiated mice were each transplanted into 3–5 secondary recipients that had been sublethally irradiated (600 Gy). Depending on the number of cells obtained from the primary transplanted mice, 0.6–1.5×106 cells were transplanted and leukemias developed within 2–10 weeks suggesting fully transformed leukemic stem cells were present in the BM. The latency period in the secondary transplanted mice was similar to that seen in the primary recipients and the median survival time was ∼ 30 days (Figure 3A). The immunophenotype of the secondary transplanted mice was also similar to that in the primary mice (Figure 3B). Because all secondary transplanted mice simultaneously developed transplantable myeloid and B-lineage disease suggests that the disease initiates from progenitor cells or stem cells.

Bottom Line: Constitutive activation of FGFR1, through rearrangement with various dimerization domains, leads to atypical myeloproliferative disorders where, although T cell lymphoma are common, the BCR-FGFR1 chimeric kinase results in CML-like leukemia.The B220(-) phenotype was retained in one of the cell lines while the other was B220(+).When the two cell lines were transplanted into syngeneic mice, all animals developed the same B-lymphoblastic leukemia within 2-weeks.

View Article: PubMed Central - PubMed

Affiliation: Georgia Health Sciences University Cancer Center, Georgia Health Sciences University School of Medicine, Augusta, Georgia, United States of America.

ABSTRACT
Constitutive activation of FGFR1, through rearrangement with various dimerization domains, leads to atypical myeloproliferative disorders where, although T cell lymphoma are common, the BCR-FGFR1 chimeric kinase results in CML-like leukemia. As with the human disease, mouse bone marrow transduction/transplantation with BCR-FGFR1 leads to CML-like myeloproliferation as well as B-cell leukemia/lymphoma. The murine disease described in this report is virtually identical to the human disease in that both showed bi-lineage involvement of myeloid and B-cells, splenomegaly, leukocytosis and bone marrow hypercellularity. A CD19(+) IgM(-) CD43(+) immunophenotype was seen both in primary tumors and two cell lines derived from these tumors. In all primary tumors, subpopulations of these CD19(+) IgM(-) CD43(+) were also either B220(+) or B220(-), suggesting a block in differentiation at the pro-B cell stage. The B220(-) phenotype was retained in one of the cell lines while the other was B220(+). When the two cell lines were transplanted into syngeneic mice, all animals developed the same B-lymphoblastic leukemia within 2-weeks. Thus, the murine model described here closely mimics the human disease with bilineage myeloid and B-cell leukemia/lymphoma which provides a representative model to investigate therapeutic intervention and a better understanding of the etiology of the disease.

Show MeSH
Related in: MedlinePlus