ETV6–FLT3 fusion gene-positive, eosinophilia-associated myeloproliferative neoplasm successfully treated with sorafenib and allogeneic stem cell transplant
Lorenzo FalchiMeenakshi MehrotraKate J. NewberryLindsey LyleGary LuKeyur P. PatelRajyalakshmi LuthraUday PopatSrđan Verstovšek
39
Citation
13
Reference
10
Related Paper
Citation Trend
Keywords:
Myeloproliferative neoplasm
Neoplasm
ETV6
Hematology
Rearrangements of 12p, resulting from deletions or translocations, are common findings in hematologic malignancies. In many cases, these rearrangements target the ETV6 gene (previously called TEL) located at 12p13. Various partner genes have been implicated in the formation of fusion genes with ETV6. These include PDGFRB, JAK2, NTRK3, ABL2, and ABL1, each of which encodes for proteins with tyrosine kinase activity. To date, ETV6/ABL1 transcripts have been detected in only four patients with a leukemic disorder. Here, we describe one adult with chronic myeloid leukemia and a child with T-cell acute lymphocytic leukemia with ETV6/ABL1. Molecular cytogenetic analysis confirmed that formation of an ETV6/ABL1 fusion in these patients required at least three chromosomal breaks and showed that each of these translocations is the result of a complex chromosomal rearrangement. Molecular analysis showed the presence of two fusion transcripts in both patients as the result of alternative splicing, questioning the suggested role of these transcripts in the lineage specificity. Clinical findings of these patients were compared to those of previously reported cases, and the possible clinical and biological similarities between ETV6/ABL1 and other fusion genes leading to increased tyrosine kinase activity are discussed.
ETV6
PDGFRB
ABL
Gene rearrangement
Chimeric gene
Cite
Citations (106)
Secretory carcinoma (SC) is a low-grade salivary gland carcinoma similar to secretory breast carcinoma harboring the ETV6-NTRK3 fusion gene, that was first proposed as a distinct disease entity in 2010 by Skálová et al. SC has heterogeneous histopathological manifestations, so that definitive diagnosis of the tumor by histopathological examination is difficult. Many fusion partners of ETV6 are known in other malignant tumors. In the case of SC also, previously unknown fusion partners of ETV6 (ETV6-X) have been reported recently. Herein, we report a case of SC of the submandibular gland harboring an ETV6-X fusion gene. A 32-year-old man presented to our department with a mass in his right submandibular region that he had first noticed one month earlier. We diagnosed the mass as a submandibular gland tumor and performed submandibular gland excision. The postoperative histopathological findings led to suspicion of the tumor as a SC. Subsequently, FISH analysis led to a confirmed the diagnosis of SC with an ETV6-X fusion gene. No evidence of recurrence was noted during postoperative follow-up of the patient for 20 months without any further therapy. Because of the difficulty in the histological diagnosis and absence of any availability of established treatments for tumors harboring the NTRK family genes, it is important to perform genetic examination for confirmatory diagnosis in patients with suspected SC.
ETV6
Chimeric gene
Cite
Citations (0)
Background: Secretory carcinoma (SC), originally described as mammary analogue SC, is a predominantly low-grade salivary gland neoplasm characterized by a recurrent t(12;15)(p13;q25) translocation, resulting in ETV6-NTRK3 gene fusion. Recently, alternative ETV6-RET , ETV6-MAML3 , and ETV6-MET fusions have been found in a subset of SCs lacking the classic ETV6-NTRK3 fusion transcript, but still harboring ETV6 gene rearrangements. Design: Forty-nine cases of SC revealing typical histomorphology and immunoprofile were analyzed by next-generation sequencing using the FusionPlex Solid Tumor kit (ArcherDX). All 49 cases of SC were also tested for ETV6 , RET , and NTRK3 break by fluorescence in situ hybridization and for the common ETV6-NTRK3 fusions using reverse transcription polymerase chain reaction. Results: Of the 49 cases studied, 37 (76%) occurred in the parotid gland, 7 (14%) in the submandibular gland, 2 (4%) in the minor salivary glands, and 1 (2%) each in the nasal mucosa, facial skin, and thyroid gland. SCs were diagnosed more frequently in males (27/49 cases; 55%). Patients’ age at diagnosis varied from 15 to 80 years, with a mean age of 49.9 years. By molecular analysis, 40 cases (82%) presented the classic ETV6-NTRK3 fusion, whereas 9 cases (18%) revealed an alternate fusion. Of the 9 cases negative for the ETV6-NTRK3 fusion, 8 cases presented with ETV6-RET fusion. In the 1 remaining case in the parotid gland, next-generation sequencing analysis identified a novel VIM-RET fusion transcript. In addition, the analysis indicated that 1 recurrent high-grade case in the submandibular gland was positive for both ETV6-NTRK3 and MYB-SMR3B fusion transcripts. Conclusions: A novel finding in our study was the discovery of a VIM-RET fusion in 1 patient with SC of the parotid gland who could possibly benefit from RET -targeted therapy. In addition, 1 recurrent high-grade case was shown to harbor 2 different fusions, namely, ETV6-NTRK3 and MYB-SMR3B . The expanded molecular spectrum provides a novel insight into SC oncogenesis and carries important implications for molecular diagnostics, as this is the first SC-associated translocation with a non- ETV6 5′ fusion partner. This finding further expands the definition of SC while carrying implications for selecting the appropriate targeted therapy.
ETV6
Gene rearrangement
Fusion transcript
Cite
Citations (76)
A fusion gene that results from a chromosomal translocation t(9;12)(p24;p13) which fuses the 5' half of the ETV6 gene to the 3' portion of the JAK2 gene. This fusion is associated with acute myeloid and lymphoid leukemias.
ETV6
Cite
Citations (0)
Since the publication of the third edition, the WHO classification of tumors of hematopoietic and lymphoid disorders has introduced the disease entity of 'myeloid/lymphoid neoplasms with eosinophilia and PDGFRB rearrangement', in which the most common chromosomal abnormality is t(5;12) (q32;p13.2), and this abnormality generates the ETV6::PDGFRB fusion gene. However, there have been patients with hematologic features and chromosomal abnormalities that are extremely similar to those carrying ETV6::PDGFRB fusion. These rare disorders harbor ETV6::ACSL6 fusion, and only sporadic cases have been reported at present. We report a patient with chronic eosinophilic leukemia (CEL) carrying chromosome translocation t(5;12)(q32;p13.2), and we present the clinical features. In addition, we conducted a literature review to collect all reported cases and summarized the genetic and clinical profiling as well as the treatments and outcomes. In addition to our patient, a total of 19 cases have been previously reported, including 6 variants of ETV6::ACSL6 and 3 reciprocals. We identified a novel variant of the ETV6::ACSL6 transcript in our patient, and the breakpoint was flanked by exon 2 of ETV6 and exon 2 of ACSL6. The cellular morphology features consisted of myeloproliferative neoplasm (MPN); myelodysplastic/myeloproliferative neoplasm (MDS/MPN), specifically CEL; and acute myelocytic leukemia (AML). The treatments and outcomes varied greatly depending on the type of disease, although tyrosine kinase inhibitors (TKIs) were not effective. In contrast to neoplasms with ETV6::PDGFRB fusion, myeloid neoplasms with ETV6::ACSL6 fusion have unique characteristics.
PDGFRB
ETV6
Myeloproliferative neoplasm
Hematopathology
Cite
Citations (4)
Within a cohort of 1,915 consecutive patients with myeloproliferative neoplasm followed for a median time of 5.2 years (range 0–33.3), we investigated the occurrence of lymphoid neoplasm with the aim of defining this risk and to investigate the role of genetic predisposing factors. We identified 22 patients with myeloproliferative neoplasm who developed lymphoid neoplasm over their lifetime. We found that the risk of developing lymphoid neoplasm was 2.79-fold higher (95% CI, 1.80–4.33; P
Myeloproliferative neoplasm
Neoplasm
Myeloproliferative Disorders
Cite
Citations (67)
ETV6
Gene rearrangement
Chimeric gene
Cite
Citations (85)
Abstract Background: ETV6-ABL (TEL-ABL) fusion gene is a rare but recurrent genetic aberration found in hematologic malignancies including myeloproliferative neoplasm, acute myeloid leukemia and acute lymphoblastic leukemia. As a infrequent fusion gene, there is no special treatment guideline for the diseases it causes. Methods: A case of a 42-year old man was reported, who presented fever with a markedly leukocytosis and CML-like marrow without BCR-ABL. Fusion gene was detected by RT-PCR and confirmed by direct sequencing. ETV6-ABL mRNA expressions in each cell population were determined by real-time RT-PCR in sorted peripheral blood cells. Results: ETV6-ABL fusion gene was detected by RT-PCR in the bone marrow cells. The type A of ETV6-ABL was confirmed by direct sequencing. The ratio of ETV6-ABL fusion gene transcript level in polymorphonuclear was nearly 3.6 relative to total cells, which was significantly higher than other cells. His blood routine returned to normal after three months of treatment with imatinib at 400mg daily dose. After 6 months for TKI treatment, the ratio of ETV6-ABL/ABL decreased from 174.1% to 1.882%. Conclusion: ETV6-ABL fusion gene conferred a granulocyte proliferation bias and responded to TKI therapy.
ETV6
ABL
Myeloproliferative neoplasm
Leukocytosis
Gene rearrangement
Fusion transcript
Cite
Citations (0)
Myeloproliferative neoplasm with eosinophilia and T-lymphoblastic lymphoma with ETV6–LYN gene fusion
Myeloproliferative neoplasms (MPNs) are a heterogeneous group of clonal haematopoietic stem cell disorders characterised by proliferation and maturation of different myeloid cell lineages. Classical MPNs are largely characterised by somatic mutation of JAK2, CALR or occasionally MPL genes.1, 2 MPNs can develop from chromosomal translocations forming gene fusions, involving constitutive activation and aberrant expression of tyrosine kinase (TK). Other than the BCR-ABL1 rearrangement in chronic myeloid leukaemia, gene fusions involving TK proto-oncogenes are rare in MPN but when detected, provide compelling disease-specific therapeutic targets.3 Myeloproliferative and lymphoid neoplasms with eosinophilia and specific TK gene fusions are a recently described, rare entity of clinical significance due to varying responsiveness to tyrosine kinase inhibitors (TKIs).4 The three cytogenetic categories identified, involving fusions of PDGFRA, PDGFRB or FGFR1 with different partner genes, are thought to affect a pluripotent stem cell and have variable presentation as MPN with eosinophilia, occasionally with a T-lymphoid disease component. Excellent response rates and long-term clinical outcomes have been reported with abnormalities of PDGFRA and PDGFRB treated with imatinib, whereas disorders with FGFR1 and JAK2 gene fusions are resistant to imatinib and other TKIs. We present a case of a disease fitting within this clinical and haematological spectrum, with a chromosomal rearrangement between chromosomes 8 and 12, bearing ETV6–LYN gene fusion.
PDGFRB
Myeloproliferative neoplasm
ABL
Gene rearrangement
Hematopathology
Cite
Citations (23)
The MN1::ETV6 gene fusion resulting from t(12;22)(p13;q12) has been rarely reported in myeloid neoplasms. We describe a 69-year-old male with newly diagnosed acute myeloid leukemia (AML) with erythroid differentiation and t(12;22)(p13;q12) demonstrated by conventional chromosome studies. Subsequent fluorescence in situ hybridization studies demonstrated a balanced ETV6 gene rearrangement (at 12p13). To further characterize this translocation, whole-genome sequencing was performed which confirmed t(12;22) with breakpoints involving the MN1 and ETV6 genes. Herein, we describe our case and review the literature to summarize the clinical and laboratory findings in patients with this rare but recurrent MN1::ETV6 gene fusion observed in myeloid neoplasms. Importantly, this case expands the clinical spectrum associated with the MN1::ETV6 gene fusion to include AML with erythroid differentiation. Lastly, this case demonstrates the importance of moving toward more comprehensive molecular testing to fully characterize the driver events in neoplastic genomes.
ETV6
Fusion transcript
Gene rearrangement
Cite
Citations (1)