A Novel t(8;14)(q24;q11) Rearranged Human Cell Line as a Model for Mechanistic and Drug Discovery Studies of NOTCH1-Independent Human T-Cell Leukemia
MYC-translocated T-lineage acute lymphoblastic leukemia (T-ALL) is a rare subgroup of T-ALL associated with CDKN2A/B deletions, PTEN inactivation, and absence of NOTCH1 or FBXW7 mutations. This subtype of T-ALL has been associated with induction failure and aggressive disease. Identification of drug...
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MDPI AG
2018-10-01
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| Series: | Cells |
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| Online Access: | http://www.mdpi.com/2073-4409/7/10/160 |
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| author | Valeria Tosello Gloria Milani Annalisa Martines Nadia Macri Wouder Van Loocke Filip Matthijssens Barbara Buldini Sonia Minuzzo Deborah Bongiovanni Richard Fabian Schumacher Alberto Amadori Pieter Van Vlierberghe Erich Piovan |
| author_facet | Valeria Tosello Gloria Milani Annalisa Martines Nadia Macri Wouder Van Loocke Filip Matthijssens Barbara Buldini Sonia Minuzzo Deborah Bongiovanni Richard Fabian Schumacher Alberto Amadori Pieter Van Vlierberghe Erich Piovan |
| author_sort | Valeria Tosello |
| collection | DOAJ |
| description | MYC-translocated T-lineage acute lymphoblastic leukemia (T-ALL) is a rare subgroup of T-ALL associated with CDKN2A/B deletions, PTEN inactivation, and absence of NOTCH1 or FBXW7 mutations. This subtype of T-ALL has been associated with induction failure and aggressive disease. Identification of drug targets and mechanistic insights for this disease are still limited. Here, we established a human NOTCH1-independent MYC-translocated T-ALL cell line that maintains the genetic and phenotypic characteristics of the parental leukemic clone at diagnosis. The University of Padua T-cell acute lymphoblastic leukemia 13 (UP-ALL13) cell line has all the main features of the above described MYC-translocated T-ALL. Interestingly, UP-ALL13 was found to harbor a heterozygous R882H DNMT3A mutation typically found in myeloid leukemia. Chromatin immunoprecipitation coupled with high-throughput sequencing for histone H3 lysine 27 (H3K27) acetylation revealed numerous putative super-enhancers near key transcription factors, including MYC, MYB, and LEF1. Marked cytotoxicity was found following bromodomain-containing protein 4 (BRD4) inhibition with AZD5153, suggesting a strict dependency of this particular subtype of T-ALL on the activity of super-enhancers. Altogether, this cell line may be a useful model system for dissecting the signaling pathways implicated in NOTCH1-independent T-ALL and for the screening of targeted anti-leukemia agents specific for this T-ALL subgroup. |
| first_indexed | 2024-03-12T05:28:36Z |
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| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-12T05:28:36Z |
| publishDate | 2018-10-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-5996b0cbef42471fb2826983f845f6182023-09-03T07:03:43ZengMDPI AGCells2073-44092018-10-0171016010.3390/cells7100160cells7100160A Novel t(8;14)(q24;q11) Rearranged Human Cell Line as a Model for Mechanistic and Drug Discovery Studies of NOTCH1-Independent Human T-Cell LeukemiaValeria Tosello0Gloria Milani1Annalisa Martines2Nadia Macri3Wouder Van Loocke4Filip Matthijssens5Barbara Buldini6Sonia Minuzzo7Deborah Bongiovanni8Richard Fabian Schumacher9Alberto Amadori10Pieter Van Vlierberghe11Erich Piovan12UOC Immunologia e Diagnostica Molecolare Oncologica, Istituto Oncologico Veneto—IRCCS, Padova 35128, ItalyDepartment of Biomolecular Medicine, Ghent University, Ghent 9000, BelgiumUOC Immunologia e Diagnostica Molecolare Oncologica, Istituto Oncologico Veneto—IRCCS, Padova 35128, ItalyUOC Immunologia e Diagnostica Molecolare Oncologica, Istituto Oncologico Veneto—IRCCS, Padova 35128, ItalyDepartment of Biomolecular Medicine, Ghent University, Ghent 9000, BelgiumDepartment of Biomolecular Medicine, Ghent University, Ghent 9000, BelgiumDipartimento di Salute della Donna e del Bambino, Università degli Studi di Padova, Padova 35128, ItalyDipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche, Universita’ degli Studi di Padova, Padova 35128, ItalyDipartimento di Scienze Chirurgiche, Oncologiche e Gastroenterologiche, Universita’ degli Studi di Padova, Padova 35128, ItalyPediatric Oncology Unit of Spedali Civili di Brescia, Brescia 25123, ItalyUOC Immunologia e Diagnostica Molecolare Oncologica, Istituto Oncologico Veneto—IRCCS, Padova 35128, ItalyDepartment of Biomolecular Medicine, Ghent University, Ghent 9000, BelgiumUOC Immunologia e Diagnostica Molecolare Oncologica, Istituto Oncologico Veneto—IRCCS, Padova 35128, ItalyMYC-translocated T-lineage acute lymphoblastic leukemia (T-ALL) is a rare subgroup of T-ALL associated with CDKN2A/B deletions, PTEN inactivation, and absence of NOTCH1 or FBXW7 mutations. This subtype of T-ALL has been associated with induction failure and aggressive disease. Identification of drug targets and mechanistic insights for this disease are still limited. Here, we established a human NOTCH1-independent MYC-translocated T-ALL cell line that maintains the genetic and phenotypic characteristics of the parental leukemic clone at diagnosis. The University of Padua T-cell acute lymphoblastic leukemia 13 (UP-ALL13) cell line has all the main features of the above described MYC-translocated T-ALL. Interestingly, UP-ALL13 was found to harbor a heterozygous R882H DNMT3A mutation typically found in myeloid leukemia. Chromatin immunoprecipitation coupled with high-throughput sequencing for histone H3 lysine 27 (H3K27) acetylation revealed numerous putative super-enhancers near key transcription factors, including MYC, MYB, and LEF1. Marked cytotoxicity was found following bromodomain-containing protein 4 (BRD4) inhibition with AZD5153, suggesting a strict dependency of this particular subtype of T-ALL on the activity of super-enhancers. Altogether, this cell line may be a useful model system for dissecting the signaling pathways implicated in NOTCH1-independent T-ALL and for the screening of targeted anti-leukemia agents specific for this T-ALL subgroup.http://www.mdpi.com/2073-4409/7/10/160MYC-translocated leukemiaT-lineage acute lymphoblastic leukemiaNOTCH1-independentsuper-enhancersBRD4 inhibitiontargeted therapy |
| spellingShingle | Valeria Tosello Gloria Milani Annalisa Martines Nadia Macri Wouder Van Loocke Filip Matthijssens Barbara Buldini Sonia Minuzzo Deborah Bongiovanni Richard Fabian Schumacher Alberto Amadori Pieter Van Vlierberghe Erich Piovan A Novel t(8;14)(q24;q11) Rearranged Human Cell Line as a Model for Mechanistic and Drug Discovery Studies of NOTCH1-Independent Human T-Cell Leukemia Cells MYC-translocated leukemia T-lineage acute lymphoblastic leukemia NOTCH1-independent super-enhancers BRD4 inhibition targeted therapy |
| title | A Novel t(8;14)(q24;q11) Rearranged Human Cell Line as a Model for Mechanistic and Drug Discovery Studies of NOTCH1-Independent Human T-Cell Leukemia |
| title_full | A Novel t(8;14)(q24;q11) Rearranged Human Cell Line as a Model for Mechanistic and Drug Discovery Studies of NOTCH1-Independent Human T-Cell Leukemia |
| title_fullStr | A Novel t(8;14)(q24;q11) Rearranged Human Cell Line as a Model for Mechanistic and Drug Discovery Studies of NOTCH1-Independent Human T-Cell Leukemia |
| title_full_unstemmed | A Novel t(8;14)(q24;q11) Rearranged Human Cell Line as a Model for Mechanistic and Drug Discovery Studies of NOTCH1-Independent Human T-Cell Leukemia |
| title_short | A Novel t(8;14)(q24;q11) Rearranged Human Cell Line as a Model for Mechanistic and Drug Discovery Studies of NOTCH1-Independent Human T-Cell Leukemia |
| title_sort | novel t 8 14 q24 q11 rearranged human cell line as a model for mechanistic and drug discovery studies of notch1 independent human t cell leukemia |
| topic | MYC-translocated leukemia T-lineage acute lymphoblastic leukemia NOTCH1-independent super-enhancers BRD4 inhibition targeted therapy |
| url | http://www.mdpi.com/2073-4409/7/10/160 |
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