t(12;13)(p13;q12) ETV6/FLT3
2014-03-01 Etienne De Braekeleer , Etienne De Braekeleer , Etienne De Braekeleer Affiliation1.Cytogenetics Laboratory, Faculty of Medicine, University of Brest, France
2.Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
Clinics and Pathology
Disease
Acute 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.
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.
Epidemiology
All together, eleven cases of t(12;13)(p13;q12) were described.
Clinics
Three cases of t(12;13)(p13;q12) ETV6/FLT3 are reported:
A female patient aged 68 years, with a MPD with eosinophilia; she died 21 months after diagnosis.
A 60-year old man with a MPN with hypereosinophilia in accelerated phase; he died soon after diagnosis of infection and pancytopenia.
A 29-year old man who developed MPN with hypereosinophilia four weeks after autologous stem cell transplantation following a T-lymphoblastic lymphoma; he died 5 weeks after diagnosis of MPN.
Another case presents with a similar phenotype: a 49 year-old male patient, also with a MPN with eosinophilia; he died 11 months after diagnosis (and with a history of leukocytosis for last two years before diagnosis). No molecular analysis was performed (Chiyoda et al., 1994).
The case with ETV6/CDX2 involvement was a 66 year old male patient with M1 acute myeloid leukaemia (AML); he died 40 months after diagnosis.
The six other known patients with a t(12;13)(p13;q12) were two children and one 17 year-old female patient with acute lymphoblastic leukemia (ALL) (Keene et al., 1987; Wlodarska et al., 1998; Heerema et al., 2000) and three adult patients with myeloid diseases (one refractory anemia with excess of blasts (RAEB) and two AMLs; one of which was a treatment-related AML (t-AML)) (Knapp et al., 1985; Tosi et al., 1998; Clavio et al., 2001).
A female patient aged 68 years, with a MPD with eosinophilia; she died 21 months after diagnosis.
A 60-year old man with a MPN with hypereosinophilia in accelerated phase; he died soon after diagnosis of infection and pancytopenia.
A 29-year old man who developed MPN with hypereosinophilia four weeks after autologous stem cell transplantation following a T-lymphoblastic lymphoma; he died 5 weeks after diagnosis of MPN.
Another case presents with a similar phenotype: a 49 year-old male patient, also with a MPN with eosinophilia; he died 11 months after diagnosis (and with a history of leukocytosis for last two years before diagnosis). No molecular analysis was performed (Chiyoda et al., 1994).
The case with ETV6/CDX2 involvement was a 66 year old male patient with M1 acute myeloid leukaemia (AML); he died 40 months after diagnosis.
The six other known patients with a t(12;13)(p13;q12) were two children and one 17 year-old female patient with acute lymphoblastic leukemia (ALL) (Keene et al., 1987; Wlodarska et al., 1998; Heerema et al., 2000) and three adult patients with myeloid diseases (one refractory anemia with excess of blasts (RAEB) and two AMLs; one of which was a treatment-related AML (t-AML)) (Knapp et al., 1985; Tosi et al., 1998; Clavio et al., 2001).
Cytology
All three patients with ETV6/FLT3 had myeloproliferative neoplasm with eosinophilia.
Genes Involved and Proteins
Note
In three patients, the ETV6/FLT3 implication was found (Vu et al., 2006; Walz et al., 2011). 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. 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).
Gene name
ETV6 (ets variant 6)
Location
12p13.2
Note
The ETV6 gene encodes a transcription factor frequently rearranged in myeloid and lymphoid leukemias.
Dna rna description
The ETV6 gene spans a region of less than 250 kb at band 12p13.1 and consists of 8 exons. There are two start codons, one (exon 1a starting at codon 1) located at the beginning of the gene and another alternative (exon 1b starting at codon 43) upstream of exon 3.
Protein description
The ETV6 protein (452 amino acids) contains two major domains, the HLH (helix-loop-helix) and ETS domains. The HLH domain, also referred to as the pointed or sterile alpha motif domain, is encoded by exons 3 and 4 and functions as a homo-oligodimerization domain. The ETS domain, encoded by exons 6 through 8, is responsible for sequence specific DNA-binding and protein-protein interaction. Transcriptional regulator; involved in bone marrow hematopoiesis.
Gene name
FLT3 (FMS-like tyrosine kinase 3)
Location
13q12.2
Note
FLT3 is one of the most frequently mutated genes in hematologic malignancies, being found in about 30% of AML patients and rarely in ALL patients (Gilliland and Griffin, 2002; Stirewalt and Radich, 2003).
Dna rna description
The FLT3 gene spans a region of 97 kb and consists of 24 exons.
Protein description
The FLT3 gene is a member of the receptor tyrosine kinase subclass III family of genes. It encodes a protein structurally related to the receptors for platelet derived growth factor. Contains five immunoglobulin-like domains in the extracellular domain involved in protein-ligand interaction, a transmembrane domain, and an intracellular tyrosine kinase domain. Dimerization induces kinase domain activation, leading to the activation of intracellular signalling pathways. Expressed on early hemopoietic progenitor cells.
Result of the Chromosomal Anomaly
Description
Both ETV6/FLT3 and FLT3/ETV6 transcripts were detected. However, FLT3/ETV6 transcripts were out of frame. Various in frame fusion products of ETV6/FLT3 were found. Fusion of exon 5 of ETV6 5 term to exon 14 of FLT3 3 term (and exon 4 and 16 in one transcript) (Vu et al., 2006).
In-frame fusion genes were observed between exon 4 or 5 of ETV6 and exon 14 of FLT3 (Walz et al., 2011).
In-frame fusion genes were observed between exon 4 or 5 of ETV6 and exon 14 of FLT3 (Walz et al., 2011).
Schematic diagram of the ETV6, FLT3 and ETV6-FLT3 proteins.
Description
N-term Helix-loop-helix (HLH) oligodimerization domain of ETV6 fused to the transmembrane and tyrosine kinase domains of FLT3.
Oncogenesis
Constitutive tyrosine kinase activation of FLT3.
Highly cited references
| Pubmed ID | Year | Title | Citations |
|---|---|---|---|
| 35610628 | 2022 | Mutational landscape of chronic myelomonocytic leukemia in Chinese patients. | 51 |
| 33792628 | 2021 | ETV6-FLT3-positive myeloid/lymphoid neoplasm with eosinophilia presenting in an infant: an entity distinct from JMML. | 21 |
| 39587751 | 2024 | [Childhood acute lymphoblastic leukemia with CREBBP gene mutation: a clinical analysis of 14 cases]. | 21 |
| 30559310 | 2018 | Two myeloid leukemia cases with rare FLT3 fusions. | 19 |
| 34595453 | 2020 | Sorafenib Induced Complete Cytogenetic and Molecular Response in a Chronic Eosinophilic Leukemia Case with t(12;13) Translocation. | 17 |
| 29471895 | 2018 | ETV6/FLT3 Fusion Is a Novel Client Protein of Hsp90. | 12 |
| 24854988 | 2014 | ETV6-FLT3 fusion gene-positive, eosinophilia-associated myeloproliferative neoplasm successfully treated with sorafenib and allogeneic stem cell transplant. | 11 |
| 33990705 | 2021 | Myeloid/lymphoid neoplasms with FLT3 rearrangement. | 0 |
| 16761019 | 2006 | FLT3 is fused to ETV6 in a myeloproliferative disorder with hypereosinophilia and a t(12;13)(p13;q12) translocation. | 0 |
| 37985498 | 2024 | T cell phenotype and lack of eosinophilia are not uncommon in extramedullary myeloid/lymphoid neoplasms with ETV6::FLT3 fusion: a case report and review of the literature. | 0 |
| 33166908 | 2020 | Myeloid/lymphoid neoplasms with eosinophilia and FLT3 rearrangement. | 0 |
| 19345670 | 2009 | The juxtamembrane domain in ETV6/FLT3 is critical for PIM-1 up-regulation and cell proliferation. | 0 |
| 23873282 | 2014 | Successful allogeneic stem cell transplantation with long-term remission of ETV6/FLT3-positive myeloid/lymphoid neoplasm with eosinophilia. | 0 |
| 23168613 | 2013 | Direct binding of Grb2 has an important role in the development of myeloproliferative disease induced by ETV6/FLT3. | 0 |
| 21705501 | 2011 | Response of ETV6-FLT3-positive myeloid/lymphoid neoplasm with eosinophilia to inhibitors of FMS-like tyrosine kinase 3. | 0 |
Article Bibliography
| Pubmed ID | Last Year | Title | Authors |
|---|---|---|---|
| 17268528 | 2007 | Transgenic mice expressing Tel-FLT3, a constitutively activated form of FLT3, develop myeloproliferative disease. | Baldwin BR et al |
| 9920852 | 1999 | Fusion of ETV6 to the caudal-related homeobox gene CDX2 in acute myeloid leukemia with the t(12;13)(p13;q12). | Chase A et al |
| 7861615 | 1994 | [Atypical chronic myeloproliferative disorder with translocation (12;13) (p13;q12) and tumor formation]. | Chiyoda S et al |
| 11426552 | 2001 | First line therapy with fludarabine combinations in 42 patients with either post myelodysplastic syndrome or therapy related acute myeloid leukaemia. | Clavio M et al |
| 12176867 | 2002 | The roles of FLT3 in hematopoiesis and leukemia. | Gilliland DG et al |
| 11078497 | 2000 | Abnormalities of chromosome bands 13q12 to 13q14 in childhood acute lymphoblastic leukemia. | Heerema NA et al |
| 3478077 | 1987 | Abnormalities of chromosome 12p13 and malignant proliferation of eosinophils: a nonrandom association. | Keene P et al |
| 3860707 | 1985 | Cytogenetic studies in 174 consecutive patients with preleukemic or myelodysplastic syndromes. | Knapp RH et al |
| 11090077 | 2000 | Flt3 mutations from patients with acute myeloid leukemia induce transformation of 32D cells mediated by the Ras and STAT5 pathways. | Mizuki M et al |
| 8394751 | 1993 | Human FLT3/FLK2 gene: cDNA cloning and expression in hematopoietic cells. | Rosnet O et al |
| 12951584 | 2003 | The role of FLT3 in haematopoietic malignancies. | Stirewalt DL et al |
| 9523197 | 1998 | Identification of new partner chromosomes involved in fusions with the ETV6 (TEL) gene in hematologic malignancies. | Tosi S et al |
| 16761019 | 2006 | FLT3 is fused to ETV6 in a myeloproliferative disorder with hypereosinophilia and a t(12;13)(p13;q12) translocation. | Vu HA et al |
| 21705501 | 2011 | Response of ETV6-FLT3-positive myeloid/lymphoid neoplasm with eosinophilia to inhibitors of FMS-like tyrosine kinase 3. | Walz C et al |
| 9454771 | 1998 | Fluorescence in situ hybridization characterization of new translocations involving TEL (ETV6) in a wide spectrum of hematologic malignancies. | Wlodarska I et al |
Summary
Fusion gene
ETV6/FLT3 ETV6 (12p13.2) FLT3 (13q12.2) M t(12;13)(p13;q12)|ETV6/FLT3 ETV6 (12p13.2) FLT3 (13q12.2) TIC
Citation
Etienne De Braekeleer ; Etienne De Braekeleer ; Etienne De Braekeleer
t(12;13)(p13;q12) ETV6/FLT3
Atlas Genet Cytogenet Oncol Haematol. 2014-03-01
Online version: http://atlasgeneticsoncology.org/haematological/1495/t(12;13)(p13;q12)-etv6-flt3
Historical Card
2007-12-01 t(12;13)(p13;q12) ETV6/FLT3 by Jean-Loup Huret Affiliation
Genetics, Dept Medical Information, University of Poitiers, CHU Poitiers Hospital, F-86021 Poitiers, France
