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

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

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Article number10.3390/ce
JournalCells
Volume7
Issue number10
DOIs
Publication statusPublished - Oct 9 2018

Fingerprint

T-Cell Leukemia
T-cells
Drug Discovery
Precursor Cell Lymphoblastic Leukemia-Lymphoma
Cells
Cell Line
Acetylation
Cytotoxicity
Ports and harbors
Precursor T-Cell Lymphoblastic Leukemia-Lymphoma
Histones
Lysine
Chromatin
Screening
Transcription Factors
Throughput
Pharmaceutical Preparations
Mutation
Myeloid Leukemia
Chromatin Immunoprecipitation

Cite this

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. / Tosello, Valeria; Milani, Gloria; Martines, Annalisa; Macri, Nadia; Van Loocke, Wouder; Matthijssens, Filip; Buldini, Barbara; Minuzzo, Sonia; Bongiovanni, Deborah; Schumacher, Richard Fabian; Amadori, Alberto; Van Vlierberghe, Pieter; Piovan, Erich.

In: Cells, Vol. 7, No. 10, 10.3390/ce, 09.10.2018.

Research output: Contribution to journalArticle

Tosello, Valeria ; Milani, Gloria ; Martines, Annalisa ; Macri, Nadia ; Van Loocke, Wouder ; Matthijssens, Filip ; Buldini, Barbara ; Minuzzo, Sonia ; Bongiovanni, Deborah ; Schumacher, Richard Fabian ; Amadori, Alberto ; Van Vlierberghe, Pieter ; Piovan, Erich. / 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. In: Cells. 2018 ; Vol. 7, No. 10.
@article{aab318a41b6b46e79b03b715937c74aa,
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",
abstract = "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.",
author = "Valeria Tosello and Gloria Milani and Annalisa Martines and Nadia Macri and {Van Loocke}, Wouder and Filip Matthijssens and Barbara Buldini and Sonia Minuzzo and Deborah Bongiovanni and Schumacher, {Richard Fabian} and Alberto Amadori and {Van Vlierberghe}, Pieter and Erich Piovan",
year = "2018",
month = "10",
day = "9",
doi = "10.3390/cells7100160",
language = "English",
volume = "7",
journal = "Cells",
issn = "2073-4409",
publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",
number = "10",

}

TY - JOUR

T1 - 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

AU - Tosello, Valeria

AU - Milani, Gloria

AU - Martines, Annalisa

AU - Macri, Nadia

AU - Van Loocke, Wouder

AU - Matthijssens, Filip

AU - Buldini, Barbara

AU - Minuzzo, Sonia

AU - Bongiovanni, Deborah

AU - Schumacher, Richard Fabian

AU - Amadori, Alberto

AU - Van Vlierberghe, Pieter

AU - Piovan, Erich

PY - 2018/10/9

Y1 - 2018/10/9

N2 - 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.

AB - 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.

U2 - 10.3390/cells7100160

DO - 10.3390/cells7100160

M3 - Article

C2 - 30304769

VL - 7

JO - Cells

JF - Cells

SN - 2073-4409

IS - 10

M1 - 10.3390/ce

ER -