Transgenic mice expressing Tel-FLT3, a constitutively activated form of FLT3, develop myeloproliferative disease

Br, Baldwin; L, Li; Kf, Tse; Small, Sara; M, Collector; Ka, Whartenby; Sharkis, SJ; Racke, Frederick; Huso, David; Small, Donald

doi:10.1038/sj.leu.2404532

Cited by 19 publications

(26 citation statements)

References 42 publications

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“…Additional experiments confirmed the transforming properties of the ETV6-FLT3 fusion protein in Ba/F3 cells and mice. 5,6 Grand et al 7 reported a female patient with atypical chronic myeloid leukemia (CML) and an SPTBN1-FLT3 fusion who achieved long-term remission after receiving an allograft. SPTBN1-FLT3-transformed Ba/F3 cells were sensitive to several FLT3 inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Response of ETV6-FLT3–positive myeloid/lymphoid neoplasm with eosinophilia to inhibitors of FMS-like tyrosine kinase 3

Walz

Erben

Ritter³

et al. 2011

Blood

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Imatinib-resistant tyrosine kinase (TK) fusions involving FGFR1, JAK2, or FLT3 are rare but recurrent in patients with eosinophilia-associated neoplasms. We report here 2 male patients with ETV6-FLT3 ؉ myeloid/lymphoid neoplasms with eosinophilia who were treated with the multitargeted TK inhibitors sunitinib and sorafenib. Patient 1 achieved rapid complete hematologic response and complete cytogenetic response after 3 months of taking sunitinib. A secondary blast phase caused by clonal evolution was diagnosed after 6 months. He achieved a second complete hematologic response after taking sorafenib but relapsed 2 months later. An N841K point mutation within the TK domain of IntroductionEosinophilia-associated myeloid neoplasms are frequently associated with constitutive activation of disparate tyrosine kinase (TK) fusion genes. The World Health Organization's classification includes a subcategory termed "myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB or FGFR1." These cases are often characterized by the concurrent diagnosis of a myeloid neoplasm, a high-grade lymphoma (most frequently of T-cell phenotype), and eosinophilia. In the present report, we refer to this entity as MLN-eo. Other TK fusion genes, for example, involving ABL or JAK2, have also been reported in diverse eosinophilia-associated myeloid neoplasms. Excellent response rates and long-term clinical outcomes have been reported for fusions involving PDGFRA and PDGFRB after treatment with imatinib. [1][2][3] In contrast, disorders with FGFR1 and JAK2 fusion genes are resistant to imatinib and other clinically available TK inhibitors (TKIs). 4 The FMS-like tyrosine kinase 3 (FLT3) is a class III receptor TK involved in the pathogenesis of de novo acute myeloid leukemia through activation of mutations in the juxtamembrane or TK domains. These mutations are potential targets for multitargeted TKIs such as midostaurin (PKC412), sunitinib, or sorafenib, which have selective activity against FLT3 and other TKs. The efficacy of FLT3 inhibitors in acute myeloid leukemia with FLT3 mutations is currently being explored in large phase III trials. Fusion genes involving FLT3 are uncommon. Vu et al 5 characterized an ETV6-FLT3 fusion in a female patient with eosinophiliaassociated myeloproliferative neoplasm (MPN-eo) who died rapidly because of progression to blast phase. Additional experiments confirmed the transforming properties of the ETV6-FLT3 fusion protein in Ba/F3 cells and mice. 5,6 Grand et al 7 reported a female patient with atypical chronic myeloid leukemia (CML) and an SPTBN1-FLT3 fusion who achieved long-term remission after receiving an allograft. SPTBN1-FLT3-transformed Ba/F3 cells were sensitive to several FLT3 inhibitors. We here report for the first time on the efficacy of an FLT3 TKI in ETV6-FLT3 ϩ MLN-eo. Results and discussionPatient 1 was a 60-year-old man who presented with widespread lymphadenopathy and splenomegaly. Leukocytes were elevated at 14.3 ϫ 10 9 /L, with 24% eosinophils and 8% blasts. Hemoglobi...

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Section: Introductionmentioning

confidence: 99%

Response of ETV6-FLT3–positive myeloid/lymphoid neoplasm with eosinophilia to inhibitors of FMS-like tyrosine kinase 3

Walz

Erben

Ritter³

et al. 2011

Blood

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“…A significant increase in the number of CFU-GM, BFU-E, CFU-S and CFU-GEMM was produced. Mice developed MPD with a high incidence but did not succombed to leukemia (Baldwin et al, 2007).…”

Section: Leukaemia Section Mini Reviewmentioning

confidence: 99%

“…Following this report, transgenic mice expressing ETV6-FLT3 were used (Baldwin et al, 2007). Expression of the fusion protein in the transgenic mice was found in spleen, bone marrow, thymus, and liver.…”

Section: Leukaemia Section Mini Reviewmentioning

confidence: 99%

Atlas of Genetics and Cytogenetics in Oncology and Haematology, 2009, n°1 - Full issue

2011

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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“…Following the first report, transgenic mice expressing ETV6-FLT3 were used (Baldwin et al, 2007). Expression of the fusion protein in the transgenic mice was found in spleen, bone marrow, thymus, and liver.…”

Section: Notementioning

confidence: 99%

“…A significant increase in the number of CFU-GM, BFU-E, CFU-S and CFU-GEMM was produced. Mice developed MPD with a high incidence but did not succumbed to leukemia (Baldwin et al, 2007).…”

Section: Notementioning

confidence: 99%

t(12;13)(p13;q12) ETV6/FLT3

Braekeleer¹,

Douet‐Guilbert²,

Braekeleer³

2017

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Review on t(12;13)(p13;q12) ETV6/FLT3, with data on clinics, and the genes implicated. Clinics and pathology DiseaseAcute lymphoblastic leukemia (ALL) and myeloid malignancies are described in cases of t(12;13)(p13;q12) Note The translocation t(12;13)(p13;q12) is molecularly heterogeneous: The t(12;13)(p13;q12) with ETV6 and FLT3 involvement, herein described, was found in three cases of myeloproliferative neoplasm (MPN) with eosinophilia (Vu et al., 2006; Walz et al., 2011). On the other hand, a t(12;13)(p13;q12) ETV6/CDX2 has been described in another case (Chase et al., 1999). Finally, other cases of t(12;13)(p13;q12) without molecular ascertainment may or may not involve FLT3, CDX2, or even ETV6. EpidemiologyAll together, eleven cases of t(12;13)(p13;q12) were described. Clinics

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Transgenic mice expressing Tel-FLT3, a constitutively activated form of FLT3, develop myeloproliferative disease

Cited by 19 publications

References 42 publications

Response of ETV6-FLT3–positive myeloid/lymphoid neoplasm with eosinophilia to inhibitors of FMS-like tyrosine kinase 3

Response of ETV6-FLT3–positive myeloid/lymphoid neoplasm with eosinophilia to inhibitors of FMS-like tyrosine kinase 3

Atlas of Genetics and Cytogenetics in Oncology and Haematology, 2009, n°1 - Full issue

t(12;13)(p13;q12) ETV6/FLT3

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