Modeling the human 8p11-myeloproliferative syndrome in immunodeficient mice

Ågerstam, Helena; Järås, Marcus; Andersson, Anna; Johnels, Petra; Hansen, Nils; Lassen, Carin; Rissler, Marianne; Gisselsson, David; Olofsson, Tor; Richter, Johan; Fan, Xiaolong; Ehinger, Mats; Fioretos, Thoas

doi:10.1182/blood-2009-05-217182

Cited by 21 publications

(25 citation statements)

References 46 publications

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“…Unfortunately, these mice failed to develop T-lymphoma, possibly because of a lack of thymus function. 52 T-lymphomas from all individual founder mice harbored activating deletions of Notch1 ( Figure 5C-D), which is similar to the findings in Ikaros-deficient mice and other murine T-ALL cell lines 33,35 and indicates that deletion mutation of Notch1 cannot be a random event. Therefore, constitutive activation of FGFR1 and Notch1 may cooperate in the development of SCLL.…”

Section: Discussionsupporting

confidence: 72%

Constitutive Notch pathway activation in murine ZMYM2-FGFR1–induced T-cell lymphomas associated with atypical myeloproliferative disease

Ren

Cowell

2011

Blood

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The ZMYM2-FGFR1 (formerly known as ZNF198-FGFR1) fusion kinase induces stem cell leukemia-lymphoma syndrome (SCLL), a hematologic malignancy characterized by rapid transformation to acute myeloid leukemia and T-lymphoblastic lymphoma. In the present study, we demonstrate frequent, constitutive activation of Notch1 and its downstream target genes in T-cell lymphomas that arose in a murine model of ZMYM2-FGFR1 SCLL. Notch up-regulation was also demonstrated in human SCLL-and FGFR1OP2- IntroductionStem cell leukemia-lymphoma syndrome (SCLL) 1 is an atypical myeloproliferative disease-associated lymphoma. 2 Hepatosplenomegaly is common in SCLL patients, and, except for some cases with B-cell acute lymphoblastic lymphoma, 3 most patients exhibit T-lymphoblastic lymphoma. The clinical course for SCLL is aggressive, with rapid transformation to acute myeloid leukemia (AML) and lymphoblastic lymphoma of common T-cell origin. [3][4][5] Conventional chemotherapy is often not effective, 3 making early allogeneic transplantation the only treatment. 6 The characteristic 8;13 reciprocal chromosome translocation 7 results in a chimeric protein consistently involving the fibroblast growth factor receptor-1 (FGFR1). 5 To date, ϳ 10 different gene partners have been shown to fuse to FGFR1, including ZMYM2, 4,7 CEP110, 8 and FGFR1OP, 9 among other more rare combinations. 10 In all cases, the fusion partner provides a dimerization domain for constitutive activation of FGFR1. ZMYM2-FGFR1 is the most common translocation, in which the zinc-finger-containing N-terminal part of ZMYM2 enables dimerization of FGFR1. 4 The FGFR1 rearrangement can be found in both myeloid and lymphoid cells in SCLL patients, suggesting a multipotent hematopoietic progenitor cell origin. Constitutive activation and mislocalization of the FGFR1 kinase leads to abnormal phosphorylation of downstream proteins such as PLC␥, PI3K, and various members of the STAT family of transcription factors. [11][12][13] We described previously a mouse model of ZMYM2-FGFR1 SCLL that closely resembles the clinical characteristics of patients with the ZMYM2-FGFR1 translocation, having a distinct myeloproliferative disorder and severe T-lymphoblastic leukemia. The constitutive and ligand-independent activation of the FGFR1 signal transduction pathway is believed to be essential for disease pathogenesis. [13][14] Evidence of tumor oligoclonality and normal differentiation of thymocytes in these animals, however, indicates that additional genetic alterations are required for disease development and progression. Array comparative genomic hybridization demonstrated Tcra and Tcrd gene deletion in leukemic cells in these animals. Lymphomas were CD4 ϩ /CD8 ϩ double-positive (DP), representing an arrest in the late stages of T-cell development, because rearrangement of Tcra is critical for these final maturation stages. However, because Tcra-null mice do not develop T-cell lymphoma, [15][16] it is clear that deletion of Tcra in itself is also not sufficient to induce T-lymphoblastic ly...

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Section: Discussionsupporting

confidence: 72%

Constitutive Notch pathway activation in murine ZMYM2-FGFR1–induced T-cell lymphomas associated with atypical myeloproliferative disease

Ren

Cowell

2011

Blood

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“…12 These results argue against NSG strains being unable to support Tlymphopoiesis after receiving transplants with human cells 41 and supports other observation of human HSC engraftment in NSG mice. 40,42 As such, the NSG model can be used to study leukemogenesis in myeloid and T-and B-lymphoid lineages.…”

Section: Cd19supporting

confidence: 80%

Dysregulated signaling pathways in the development of CNTRL-FGFR1–induced myeloid and lymphoid malignancies associated with FGFR1 in human and mouse models

Ren

Qin

Kitamura

et al. 2013

Blood

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“…However, an animal model of EMS may become a valuable tool. Recently, a humanized mouse model of EMS has been established [30]. Therefore, elucidation of the pathogenesis and development of targeted therapy will hopefully be realized in the future.…”

Section: Discussionmentioning

confidence: 99%

A Case of 8p11 Myeloproliferative Syndrome with <b><i>BCR-FGFR1</i></b> Gene Fusion Presenting with Trilineage Acute Leukemia/Lymphoma, Successfully Treated by Cord Blood Transplantation

Morishige¹,

Oku²,

Takata³

et al. 2012

Acta Haematol

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The 8p11 myeloproliferative syndrome is a rare neoplasm associated with chromosomal translocations involving the fibroblast growth factor receptor 1 (FGFR1) gene located at chromosome 8p11–12. FGFR1 encodes a transmembrane receptor tyrosine kinase. The resultant fusion proteins are constitutively active tyrosine kinases that drive the proliferation of hematopoietic cells, whose uncontrolled growth can present as a myeloproliferative neoplasm. We report here the case of a 50-year-old man harboring the t(8;22)(p12;q11) chromosomal translocation in cells from both bone marrow and lymph nodes. He presented with acute leukemia and lymphoma with trilineage features. A novel mRNA in-frame fusion between exon 4 of the breakpoint cluster region (BCR) gene at chromosome 22q11 and exon 9 of FGFR1 gene on chromosome 8p11–12 was identified by reverse transcription polymerase chain reaction analysis and was confirmed by DNA sequencing. Because the patient was refractory to chemotherapy, cord blood transplantation was performed in progressive disease. It resulted in a successful outcome in which cytogenetic complete remission has been maintained for 2 years till date.

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Modeling the human 8p11-myeloproliferative syndrome in immunodeficient mice

Abstract: The 8p11 myeloproliferative syndrome (EMS), also referred to as stem cell leukemia/lymphoma, is a chronic myeloproliferative disorder that rapidly progresses into acute leukemia. Molecularly, EMS is characterized by fusion of various partner genes to the

Cited by 21 publications

References 46 publications

Constitutive Notch pathway activation in murine ZMYM2-FGFR1–induced T-cell lymphomas associated with atypical myeloproliferative disease

Constitutive Notch pathway activation in murine ZMYM2-FGFR1–induced T-cell lymphomas associated with atypical myeloproliferative disease

Dysregulated signaling pathways in the development of CNTRL-FGFR1–induced myeloid and lymphoid malignancies associated with FGFR1 in human and mouse models

A Case of 8p11 Myeloproliferative Syndrome with <b><i>BCR-FGFR1</i></b> Gene Fusion Presenting with Trilineage Acute Leukemia/Lymphoma, Successfully Treated by Cord Blood Transplantation

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