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Familial Acute Myeloid Leukemia
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The ETS translocation variant gene 6 (ETV6) gene, located in chromosome 12p13.2 band and composed of 8 exons spanning 240 kb, encodes for a nuclear protein that functions as an ETS family transcription factor and plays a key role in hematopoiesis and development before birth [40,41]. The protein product contains an N-terminal pointed domain that is involved in protein-protein interactions with itself and other proteins, a C-terminal DNA-binding domain that is highly conserved among ETS family transcription factors, and an intervening linker region that indirectly affects the DNA binding domain. The ETV6 gene (OMIM #600618) is well-known for its involvement in several somatic chromosomal translocations in myeloid and lymphoid leukemias, in synergy with several partner genes for chromosomal fusion [41], with the ETV6-RUNX1 fusion being the most common translocation in pediatric B-lymphoblastic leukemia. In 2015, germline mutations in ETV6 in families with inherited thrombocytopenia 5 [THC5 (OMIM # 616216)] were found to be associated with diverse hematologic malignancies, including acute lymphoblastic leukemia, and occasionally, AML and myelodysplasia, multiple myeloma and non-hematologic cancer [42,43].
Fluorescence In Situ Hybridization and Polymerase Chain Reaction
Published in Wojciech Gorczyca, Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2014
ETV6 (TEL) is an important hematopoietic regulatory factor and ETV6 gene rearrangement is involved in a wide variety of hematological malignancies. The partner genes include RUNX1, JAK2, ABL2, NCOA2, SYK, and PAX5 [103]. ETV6 rearrangements are generally associated with a favorable outcome in pediatric ALL, although ETV6–ABL1 predicts poor prognosis. ETV6 rearrangement are very rare (<1%) in patients with AML or MDS.
Analysis of RBP expression and binding sites identifies PTBP1 as a regulator of CD19 expression in B-ALL
Published in OncoImmunology, 2023
Nicole Ziegler, Mariela Cortés-López, Francesca Alt, Maximilian Sprang, Arsenij Ustjanzew, Nadine Lehmann, Khalifa El Malki, Arthur Wingerter, Alexandra Russo, Olaf Beck, Sebastian Attig, Lea Roth, Julian König, Claudia Paret, Jörg Faber
Interestingly, the mutation appeared to be accumulated in B-ALL patients harboring a ETV6-RUNX1 gene fusion, as 80% of samples of this molecular subtype carried the 2-nucleotide deletion. However, a higher number of samples will be required to corroborate such correlation. Strikingly, the deletion could already be detected at diagnosis, suggesting that leukemic blasts harbor the potential to evolve into CAR-T-resistant clones directly from the beginning. With this, we pursue the idea of Rabilloud et al. who claimed the existence of CD19-negative B-ALL cells prior to CAR-T treatment.16 Interestingly, we did not find any blast-specific mutations in the coding sequence. Thus, frameshift mutations may occur later during disease development or rather under therapy and a potential correlation with the treatment regimen before CART-19 therapy should be considered.
What happens to children with acute lymphoblastic leukemia in low- and middle-income countries after relapse? A single-center experience from India
Published in Pediatric Hematology and Oncology, 2023
Richa Sharon Angel Korrapolu, Deepthi Boddu, Rikki John, Nikita Antonisamy, Tulasi Geevar, Arun Kumar Arunachalam, Leenu Lizbeth Joseph, Hema Nalapullu Srinivasan, Leni Grace Mathew, Sidharth Totadri
The study was performed in the pediatric hematology oncology unit of the Christian medical college and hospital, Vellore. The inclusion criteria were age ≤15 years (institutional cutoff to be treated by the pediatric unit), and a diagnosis of relapse during or following treatment for ALL at our center. Patients who received primary treatment elsewhere and presented only for the management of relapse to our center were excluded due to the variable availability of details of initial therapy. The study period was from January 2010 to December 2019. Data collection and analysis were performed in 2022. The diagnosis of ALL was confirmed by morphological examination of the bone marrow and flow cytometry. Details of reverse-transcriptase polymerase chain reaction to detect the fusion transcripts: ETV6::RUNX1, TCF3::PBX1, BCR::ABL1, and KMT2A::AFF1; and conventional karyotyping to identify numerical and structural chromosomal aberrations were collected from the initial diagnostic work up. Poor-risk genetics included hypodiploidy (≤39 chromosomes), BCR::ABL1 (Philadelphia chromosome), and KMT2A::AFF1. Good-risk genetics included high hyperdiploidy (51–65 chromosomes) and ETV6::RUNX1. Frontline risk stratification and treatment were based on a United Kingdom ALL (UKALL2003) backbone and the authors have previously published the approach.6
Myeloid neoplasm with ETV6::ACSl6 fusion: landscape of molecular and clinical features
Published in Hematology, 2022
Zhan Su, Xin Liu, Weiyu Hu, Jie Yang, Xiangcong Yin, Fang Hou, Yaqi Wang, Jinglian Zhang
The ETS variant 6 gene (ETV6), mapping to chromosome 12p13.2, belongs to the E-twenty-six (ETS) family of transcription factors. As a transcriptional repressor, ETV6 binds to the 5'-CCGGAAGT-3’ DNA sequence via its C-terminal DNA-binding domain and exerts functions in association with a plethora of corepressors, i.e. SIN3A, NCOR, and HDAC3. ETV6 is ubiquitously expressed in a broad spectrum of tissues, including bone marrow. ETV6 is essential for maintaining hematopoietic stem cell function and megakaryocyte development [15, 16]. A variety of ETV6 germline or somatic aberrations have been reported in hematologic malignancies, such as mutations, deletions, rearrangements, and fusions, demonstrating its role in leukemogenesis [17, 18]. Acyl-CoA synthetase long chain family member 6 (ACSL6) belongs to the long-chain acyl-CoA synthetase (ACSL) family. ACSL6 catalyzes the conversion of long-chain fatty acids to their active form, acyl-CoA, together with CoA and ATP. ACSL6 is essential for fatty acid metabolism and affects mitochondrial content, respiratory rates, and lipid oxidation. ACSL6 is highly expressed in the brain, testis, and bone marrow, and it has been found to be related to cell proliferation and apoptosis [19–22].