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.
Highlights
The 8p11 myeloproliferative syndrome (EMS), known as stem cell leukemia lymphoma (SCLL) syndrome, is a distinct clinico-pathological entity [1] defined by reciprocal chromosome translocations that result in a chimeric protein with constitutive activation of the kinase domain of the fibroblast growth factor receptor-1 (FGFR1)
Despite the clear involvement of the FGFR1 fusion kinases, still relatively little is known about the etiology of these diseases and the distinct phenotypes seen in patients with the rarer FGFR1 rearrangements provides an opportunity to dissect their subtle differences
We have shown the involvement of a pro-B cell in a mouse model of BCR-FGFR1 SCLL, which may guide future studies in the analysis of the human disease
Summary
The 8p11 myeloproliferative syndrome (EMS), known as stem cell leukemia lymphoma (SCLL) syndrome, is a distinct clinico-pathological entity [1] defined by reciprocal chromosome translocations that result in a chimeric protein with constitutive activation of the kinase domain of the fibroblast growth factor receptor-1 (FGFR1). The t(8;22) variant translocation, results in a fusion between BCR (breakpoint cluster region) and FGFR1 which is clinically distinct from the myeloid/T-cell neoplasms of other variant FGFR1 fusions [5,6,7,8,9,10,11]. Leukemias in these patients are clinically more similar to BCR-ABL1 induced CML, suggesting BCR may play a role in this particular pathogenesis
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