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

-translocated T-lineage acute lymphoblastic leukemia (T-ALL) is a rare subgroup of T-ALL associated with deletions, inactivation, and absence of or mutations. This subtype of T-ALL has been associated with induction failure and aggressive disease. Identification of drug targets and mechanistic insig...

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Published in:Cells (Basel, Switzerland) Switzerland), 2018-10, Vol.7 (10), p.160
Main Authors: 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
Format: Article
Language:English
Subjects:
Acetylation
Acute lymphoblastic leukemia
Apoptosis
BRD4 inhibition
Cdc4 protein
Cell cycle
Chromatin
Cytokines
Cytotoxicity
Enhancers
Gene expression
Histone H3
Histones
Hybridization
Immunoprecipitation
Leukemia
Lymphatic leukemia
Lymphocytes T
Lysine
Medical prognosis
Mutation
Myc protein
MYC-translocated leukemia
Myeloid leukemia
Next-generation sequencing
Notch1 protein
NOTCH1-independent
PTEN protein
super-enhancers
T-lineage acute lymphoblastic leukemia
targeted therapy
Therapeutic targets
Transcription factors
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Summary:-translocated T-lineage acute lymphoblastic leukemia (T-ALL) is a rare subgroup of T-ALL associated with deletions, inactivation, and absence of or 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 -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 -translocated T-ALL. Interestingly, UP-ALL13 was found to harbor a heterozygous R882H 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.
ISSN:2073-4409
2073-4409
DOI:10.3390/cells7100160