NUP98-BPTF gene fusion identified in primary refractory acute megakaryoblastic leukemia of infancy.
| Title: | NUP98-BPTF gene fusion identified in primary refractory acute megakaryoblastic leukemia of infancy. |
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| Authors: | Roussy M; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montréal, Québec, Canada.; Department of Biomedical Sciences, Université de Montréal, Montréal, Québec, Canada.; Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada.; Bilodeau M; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montréal, Québec, Canada.; Jouan L; Integrated Centre for Pediatric Clinical Genomics, CHU Sainte-Justine, Montréal, Québec, Canada.; Tibout P; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montréal, Québec, Canada.; Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada.; Laramée L; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montréal, Québec, Canada.; Lemyre E; Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada.; Cytogenetics laboratory, genetics division, CHU Sainte-Justine, Montréal, Québec, Canada.; Léveillé F; Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada.; Cytogenetics laboratory, genetics division, CHU Sainte-Justine, Montréal, Québec, Canada.; Tihy F; Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada.; Cytogenetics laboratory, genetics division, CHU Sainte-Justine, Montréal, Québec, Canada.; Cardin S; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montréal, Québec, Canada.; Sauvageau C; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montréal, Québec, Canada.; Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada.; Couture F; Molecular diagnostic laboratory, CHU Sainte-Justine, Montréal, Québec, Canada.; Louis I; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montréal, Québec, Canada.; Choblet A; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montréal, Québec, Canada.; Patey N; Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada.; Department of Pathology, CHU Sainte-Justine, Montréal, Québec, Canada.; Gendron P; Bioinformatics Core Facility, Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, Québec, Canada.; Duval M; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montréal, Québec, Canada.; Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada.; Teira P; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montréal, Québec, Canada.; Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada.; Hébert J; Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada.; Division of Hematology, Maisonneuve-Rosemont Hospital, Montréal, Québec, Canada.; Québec Leukemia Cell Bank, Maisonneuve-Rosemont Hospital, Montréal, Québec, Canada.; Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, Québec, Canada.; Wilhelm BT; Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada.; Institute for Research in Immunology and Cancer (IRIC), Université de Montréal, Montréal, Québec, Canada.; Laboratory for high throughput biology, IRIC, Université de Montréal, Montréal, Québec, Canada.; Choi JK; Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.; Gruber TA; Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.; Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee.; Bittencourt H; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montréal, Québec, Canada.; Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada.; Cellot S; Pediatric Hematology-Oncology Division, Charles-Bruneau Cancer Center, CHU Sainte-Justine Research Center, Montréal, Québec, Canada.; Faculty of Medicine, Université de Montréal, Montréal, Québec, Canada.; Québec Leukemia Cell Bank, Maisonneuve-Rosemont Hospital, Montréal, Québec, Canada. |
| Source: | Genes, chromosomes & cancer [Genes Chromosomes Cancer] 2018 Jun; Vol. 57 (6), pp. 311-319. Date of Electronic Publication: 2018 Mar 28. |
| Publication Type: | Case Reports; Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: Wiley-Liss Country of Publication: United States NLM ID: 9007329 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1098-2264 (Electronic) Linking ISSN: 10452257 NLM ISO Abbreviation: Genes Chromosomes Cancer Subsets: MEDLINE |
| Imprint Name(s): | Publication: New York, NY : Wiley-Liss; Original Publication: New York : A.R. Liss, c1989- |
| MeSH Terms: | Antigens, Nuclear/*genetics ; Leukemia, Megakaryoblastic, Acute/*genetics ; Nerve Tissue Proteins/*genetics ; Nuclear Pore Complex Proteins/*genetics ; Transcription Factors/*genetics; Drug Resistance, Neoplasm/genetics ; Leukemia, Megakaryoblastic, Acute/drug therapy ; Disease Progression ; Gene Expression Profiling ; Humans ; Infant ; Karyotyping ; Male ; RNA Splicing ; Bromodomain Containing Proteins |
| Abstract: | The advent of large scale genomic sequencing technologies significantly improved the molecular classification of acute megakaryoblastic leukaemia (AMKL). AMKL represents a subset (∼10%) of high fatality pediatric acute myeloid leukemia (AML). Recurrent and mutually exclusive chimeric gene fusions associated with pediatric AMKL are found in 60%-70% of cases and include RBM15-MKL1, CBFA2T3-GLIS2, NUP98-KDM5A and MLL rearrangements. In addition, another 4% of AMKL harbor NUP98 rearrangements (NUP98r), with yet undetermined fusion partners. We report a novel NUP98-BPTF fusion in an infant presenting with primary refractory AMKL. In this NUP98r, the C-terminal chromatin recognition modules of BPTF, a core subunit of the NURF (nucleosome remodeling factor) ATP-dependent chromatin-remodeling complex, are fused to the N-terminal moiety of NUP98, creating an in frame NUP98-BPTF fusion, with structural homology to NUP98-KDM5A. The leukemic blasts expressed two NUP98-BPTF splicing variants, containing one or two tandemly spaced PHD chromatin reader domains. Our study also identified an unreported wild type BPTF splicing variant encoding for 2 PHD domains, detected both in normal cord blood CD34+ cells and in leukemic blasts, as with the fly BPTF homolog, Nurf301. Disease course was marked by rapid progression and primary chemoresistance, with ultimately significant tumor burden reduction following treatment with a clofarabine containing regimen. In sum, we report 2 novel NUP98-BPTF fusion isoforms that contribute to refine the NUP98r subgroup of pediatric AMKL. Multicenter clinical trials are critically required to determine the frequency of this fusion in AMKL patients and explore innovative treatment strategies for a disease still plagued with poor outcomes.; (© 2018 Wiley Periodicals, Inc.) |
| Contributed Indexing: | Keywords: AMKL; AML; BPTF; Chimeric oncogenes; NUP98 |
| Substance Nomenclature: | 0 (Antigens, Nuclear); 0 (Nerve Tissue Proteins); 0 (Nuclear Pore Complex Proteins); 0 (Transcription Factors); 0 (Nup98 protein, human); 0 (fetal Alzheimer antigen); 0 (Bromodomain Containing Proteins) |
| Entry Date(s): | Date Created: 20180211 Date Completed: 20180927 Latest Revision: 20260127 |
| Update Code: | 20260130 |
| DOI: | 10.1002/gcc.22532 |
| PMID: | 29427526 |
| Database: | MEDLINE |
Case Reports; Journal Article; Research Support, Non-U.S. Gov't