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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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A mouse model of BCR-FGFR1 induced leukemia is consistent with the human disease.(A) May-Grünwald-Giemsa staining of peripheral blood showing an increase of white blood cells and the presence of blasts with a more mature myeloid chronic-like phenotype from mouse #1 (above) and a more blast-like phenotype from mouse #5 (below) compared with BM from mice reconstituted with the MIEG3 vector. (B) Survival curves for mice receiving either 900 centiGray or 600 centiGray shows a longer latency period for the lower dose and longer survival compared with MIEG3 controls. (C) The average spleen and liver weight of BCR-FGFR1 recipients (n = 8) were significantly increased compared to MIEG3 mice (n = 5), (** p<0.01). (D) BCR-FGFR1 induced leukemia characterized by (i) hepatosplenomegaly and visible splenic fibrosis, (ii) pulmonary infiltration, enlarged Peyer’s patches (iii, arrows) and a mesenteric lymph node (iv, arrow). Molecular imaging of GFP defined tumor cell populations in the liver (v), Peyer’s patches (vi) and spleen (vii). (D) H&E stained BCR-FGFR1 recipient tissues shows hypercellular bone marrow with a predominant increase in myeloid and megakaryocytic lineages, spleen with extramedullary myeloid proliferation including dysplastic megakaryocytes (middle) and infiltrating myeloid cells in the lung which is consistent with D (ii). Tissues from control animals are shown below for comparison.
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pone-0038265-g001: A mouse model of BCR-FGFR1 induced leukemia is consistent with the human disease.(A) May-Grünwald-Giemsa staining of peripheral blood showing an increase of white blood cells and the presence of blasts with a more mature myeloid chronic-like phenotype from mouse #1 (above) and a more blast-like phenotype from mouse #5 (below) compared with BM from mice reconstituted with the MIEG3 vector. (B) Survival curves for mice receiving either 900 centiGray or 600 centiGray shows a longer latency period for the lower dose and longer survival compared with MIEG3 controls. (C) The average spleen and liver weight of BCR-FGFR1 recipients (n = 8) were significantly increased compared to MIEG3 mice (n = 5), (** p<0.01). (D) BCR-FGFR1 induced leukemia characterized by (i) hepatosplenomegaly and visible splenic fibrosis, (ii) pulmonary infiltration, enlarged Peyer’s patches (iii, arrows) and a mesenteric lymph node (iv, arrow). Molecular imaging of GFP defined tumor cell populations in the liver (v), Peyer’s patches (vi) and spleen (vii). (D) H&E stained BCR-FGFR1 recipient tissues shows hypercellular bone marrow with a predominant increase in myeloid and megakaryocytic lineages, spleen with extramedullary myeloid proliferation including dysplastic megakaryocytes (middle) and infiltrating myeloid cells in the lung which is consistent with D (ii). Tissues from control animals are shown below for comparison.

Mentions: Donor bone marrow (BM) from three individual Balb/c founder mice were transduced with the BCR-FGFR1-containing MIEG3 viral vector which was then transplanted into 5 lethally irradiated (900 cGy) recipient mice. To investigate the effect of irradiation dose on disease development, we also independently infected BM cells from an additional 5 donor mice with BCR-FGFR1 retro-supernatant. These infected BM cells were transplanted into 5 sublethally irradiated (600 cGy) recipients. One mouse in this group died from irradiation shortly after transplantation and no obvious disease development was noted. Approximately 2-weeks following the primary transplantation, analysis of peripheral blood samples from these animals showed that the WBC count in the peripheral blood began to reconstitute and increase, suggesting successful engraftment. By 3 to 4 weeks post-transplantation the WBC count was remarkably increased in all lethally irradiated recipients (Figure 1A). Abnormal leukocytes with ring-shaped nuclei and blast cells were frequently seen in this cohort of mice (Figure 1A), indicative of the development of leukemia. The increase of WBC count or abnormal leukocytes were only seen after ∼2 months post-transplantation in sublethally irradiated recipients. The median survival time in the lethally irradiated cohort (n = 5) was 30±6.5 days post-transplantation, while the 600 cGy cohort (n = 4) it was 83±52.5 days (Figure 1B). Except for this longer latency period, we did not observe any differences between lethally and sublethally irradiated recipients based on their immunophenotypes (see below). Five mice transduced and transplanted with the empty MIEG3 vector did not develop disease over a one year observational period.


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)

A mouse model of BCR-FGFR1 induced leukemia is consistent with the human disease.(A) May-Grünwald-Giemsa staining of peripheral blood showing an increase of white blood cells and the presence of blasts with a more mature myeloid chronic-like phenotype from mouse #1 (above) and a more blast-like phenotype from mouse #5 (below) compared with BM from mice reconstituted with the MIEG3 vector. (B) Survival curves for mice receiving either 900 centiGray or 600 centiGray shows a longer latency period for the lower dose and longer survival compared with MIEG3 controls. (C) The average spleen and liver weight of BCR-FGFR1 recipients (n = 8) were significantly increased compared to MIEG3 mice (n = 5), (** p<0.01). (D) BCR-FGFR1 induced leukemia characterized by (i) hepatosplenomegaly and visible splenic fibrosis, (ii) pulmonary infiltration, enlarged Peyer’s patches (iii, arrows) and a mesenteric lymph node (iv, arrow). Molecular imaging of GFP defined tumor cell populations in the liver (v), Peyer’s patches (vi) and spleen (vii). (D) H&E stained BCR-FGFR1 recipient tissues shows hypercellular bone marrow with a predominant increase in myeloid and megakaryocytic lineages, spleen with extramedullary myeloid proliferation including dysplastic megakaryocytes (middle) and infiltrating myeloid cells in the lung which is consistent with D (ii). Tissues from control animals are shown below for comparison.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3368885&req=5

pone-0038265-g001: A mouse model of BCR-FGFR1 induced leukemia is consistent with the human disease.(A) May-Grünwald-Giemsa staining of peripheral blood showing an increase of white blood cells and the presence of blasts with a more mature myeloid chronic-like phenotype from mouse #1 (above) and a more blast-like phenotype from mouse #5 (below) compared with BM from mice reconstituted with the MIEG3 vector. (B) Survival curves for mice receiving either 900 centiGray or 600 centiGray shows a longer latency period for the lower dose and longer survival compared with MIEG3 controls. (C) The average spleen and liver weight of BCR-FGFR1 recipients (n = 8) were significantly increased compared to MIEG3 mice (n = 5), (** p<0.01). (D) BCR-FGFR1 induced leukemia characterized by (i) hepatosplenomegaly and visible splenic fibrosis, (ii) pulmonary infiltration, enlarged Peyer’s patches (iii, arrows) and a mesenteric lymph node (iv, arrow). Molecular imaging of GFP defined tumor cell populations in the liver (v), Peyer’s patches (vi) and spleen (vii). (D) H&E stained BCR-FGFR1 recipient tissues shows hypercellular bone marrow with a predominant increase in myeloid and megakaryocytic lineages, spleen with extramedullary myeloid proliferation including dysplastic megakaryocytes (middle) and infiltrating myeloid cells in the lung which is consistent with D (ii). Tissues from control animals are shown below for comparison.
Mentions: Donor bone marrow (BM) from three individual Balb/c founder mice were transduced with the BCR-FGFR1-containing MIEG3 viral vector which was then transplanted into 5 lethally irradiated (900 cGy) recipient mice. To investigate the effect of irradiation dose on disease development, we also independently infected BM cells from an additional 5 donor mice with BCR-FGFR1 retro-supernatant. These infected BM cells were transplanted into 5 sublethally irradiated (600 cGy) recipients. One mouse in this group died from irradiation shortly after transplantation and no obvious disease development was noted. Approximately 2-weeks following the primary transplantation, analysis of peripheral blood samples from these animals showed that the WBC count in the peripheral blood began to reconstitute and increase, suggesting successful engraftment. By 3 to 4 weeks post-transplantation the WBC count was remarkably increased in all lethally irradiated recipients (Figure 1A). Abnormal leukocytes with ring-shaped nuclei and blast cells were frequently seen in this cohort of mice (Figure 1A), indicative of the development of leukemia. The increase of WBC count or abnormal leukocytes were only seen after ∼2 months post-transplantation in sublethally irradiated recipients. The median survival time in the lethally irradiated cohort (n = 5) was 30±6.5 days post-transplantation, while the 600 cGy cohort (n = 4) it was 83±52.5 days (Figure 1B). Except for this longer latency period, we did not observe any differences between lethally and sublethally irradiated recipients based on their immunophenotypes (see below). Five mice transduced and transplanted with the empty MIEG3 vector did not develop disease over a one year observational period.

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