A Tumor Suppressor Enhancer of<i>PTEN</i>in T-cell Development and Leukemia

Tottone, Luca; Lancho, Olga; Loh, Jui-Wan; Singh, Amartya; Kimura, Shunsuke; Roels, Juliette; Kuchmiy, Anna; Strubbe, Steven; Lawlor, Matthew A.; Silva-Diz, Victoria da; Luo, Shirley; Gachet, Stéphanie; García-Prieto, Carlos A.; Hagelaar, Rico; Esteller, Manel; Meijerink, Jules P.P.; Soulier, Jean; Taghon, Tom; Vlierberghe, Pieter Van; Mullighan, Charles G.; Khiabanian, Hossein; Rocha, Pedro P.; Herranz, Daniel

doi:10.1158/2643-3230.bcd-20-0201

Cited by 18 publications

(13 citation statements)

References 87 publications

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“…Our finding of a novel NOTCH1-bound SIRT1 enhancer (N-Se) adds to the growing literature of relevant enhancers in T-ALL, including the N-Me MYC enhancer (44), the PE PTEN enhancer (47) or the de novo acquired enhancers for TAL1 (71) and BCL11B (72), among others (73). Our results unequivocally demonstrate that N-Se regulates SIRT1 levels.…”

Section: Discussionsupporting

confidence: 74%

“…We performed reporter assays using a pGL4.10 Vector (Promega, E6651) luciferase construct alone or coupled with the N-Se enhancer sequence (hg19; chr10:69,608,815–69,610,235; DNA sequence was synthesized by Genewiz), cloned in the forward and reverse orientations, and following our previously described protocol (47). Briefly, we electroporated JURKAT cells with a Neon Transfection System Device (MPK5000, Thermo Fisher Scientific) using 100 μL tips (MPK10025, Thermo Fisher Scientific).…”

Section: Methodsmentioning

confidence: 99%

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A therapeutically targetable NOTCH1-SIRT1-KAT7 axis in T-cell Leukemia

Lancho

Singh

Silva-Diz

et al. 2022

Preprint

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T-cell Acute Lymphoblastic Leukemia (T-ALL) is a NOTCH1-driven disease in need of novel therapies. Here, we identify a NOTCH1-SIRT1-KAT7 link as a therapeutic vulnerability in T-ALL, in which SIRT1 is overexpressed downstream of a novel NOTCH1-bound enhancer. SIRT1 loss impairs leukemia generation, while SIRT1 overexpression accelerates leukemia and confers resistance to NOTCH1 inhibition in a deacetylase-dependent manner. Moreover, secondary SIRT1 loss extends survival and synergizes with NOTCH1 inhibition. Global acetyl-proteomics upon SIRT1 loss uncovered hyperacetylation of KAT7 and BRD1, subunits of a histone acetyltransferase complex targeting H4K12. Metabolic and gene expression profiling revealed a metabolic crisis together with a transcriptional signature resembling KAT7 deletion. Consistently, SIRT1 loss resulted in reduced H4K12ac, and overexpression of a non-acetylatable KAT7 mutant partly rescued SIRT1 loss-induced proliferation defects. The newly unveiled NOTCH1-SIRT1-KAT7 axis uncovers novel therapeutic targets in T-ALL and reveals a circular feedback mechanism balancing deacetylase/acetyltransferase activation with potentially broad relevance in cancer.

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Section: Discussionsupporting

confidence: 74%

Section: Methodsmentioning

confidence: 99%

A therapeutically targetable NOTCH1-SIRT1-KAT7 axis in T-cell Leukemia

Lancho

Singh

Silva-Diz

et al. 2022

Preprint

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“…The validity of the screen is exemplified by a narrow intronic CIS region in Rnls , which has a Hi-C connection to the ∼400 kb distant Pten promoter ( Figure 3 A) and was recently described as a Pten enhancer. 53 Using global run-on sequencing (GRO-seq), we examined the relevance of this RE in human T-ALL patient data ( Figure 3 B) and found cell-type-specific enhancer activity, with enhancer RNA signal peaks being present in T-ALL patients but not in HEK293T cells. Accordingly, CRISPR-Cas9-based deletion of the 7–8 kb RE region led to a stronger decrease of PTEN expression in human and murine T cells (34% and 24% reduction) than in HEK293 cells (15% reduction) ( Figure 3 C).…”

Section: Resultsmentioning

confidence: 99%

In vivo interrogation of regulatory genomes reveals extensive quasi-insufficiency in cancer evolution

et al. 2023

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“…Deletions and/or loss-of-function mutations of PTEN, the main negative regulator of the PI3K/AK/mTOR pathway, were first described in 2007 [100], and linked to resistance to NOTCH1 inhibition in T-ALL cell lines [101]. An additional mechanism of PTEN inactivation has been recently found in about 1% of T-ALL, where a 200Kb-1.4Mb deletion, downstream PTEN, abrogates the activity of a highly conserved enhancer that modulates PTEN transcription [102]. Overall, PTEN haploinsufficiency/inactivation occurs in 10-15% of cases [8,102,103], is almost exclusively associated with abnormalities of the TAL/LMO subgroup (~20% of cases), and rarely cooccur with NOTCH1/FBXW7 mutations [104].…”

Section: Pi3k/akt/mtor Signaling Predicts Glucocorticoid Resistancementioning

confidence: 99%

“…An additional mechanism of PTEN inactivation has been recently found in about 1% of T-ALL, where a 200Kb-1.4Mb deletion, downstream PTEN, abrogates the activity of a highly conserved enhancer that modulates PTEN transcription [102]. Overall, PTEN haploinsufficiency/inactivation occurs in 10-15% of cases [8,102,103], is almost exclusively associated with abnormalities of the TAL/LMO subgroup (~20% of cases), and rarely cooccur with NOTCH1/FBXW7 mutations [104]. While PTEN mutations have not been associated with the prognosis, deletions appear to predict lower event-free and overall survival [21,105,106].…”

Section: Pi3k/akt/mtor Signaling Predicts Glucocorticoid Resistancementioning

confidence: 99%

T-Cell Acute Lymphoblastic Leukemia: Biomarkers and Their Clinical Usefulness

Bardelli

Arniani

Pierini

et al. 2021

Genes

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T-cell acute lymphoblastic leukemias (T-ALL) are immature lymphoid tumors localizing in the bone marrow, mediastinum, central nervous system, and lymphoid organs. They account for 10–15% of pediatric and about 25% of adult acute lymphoblastic leukemia (ALL) cases. It is a widely heterogeneous disease that is caused by the co-occurrence of multiple genetic abnormalities, which are acquired over time, and once accumulated, lead to full-blown leukemia. Recurrently affected genes deregulate pivotal cell processes, such as cycling (CDKN1B, RB1, TP53), signaling transduction (RAS pathway, IL7R/JAK/STAT, PI3K/AKT), epigenetics (PRC2 members, PHF6), and protein translation (RPL10, CNOT3). A remarkable role is played by NOTCH1 and CDKN2A, as they are altered in more than half of the cases. The activation of the NOTCH1 signaling affects thymocyte specification and development, while CDKN2A haploinsufficiency/inactivation, promotes cell cycle progression. Among recurrently involved oncogenes, a major role is exerted by T-cell-specific transcription factors, whose deregulated expression interferes with normal thymocyte development and causes a stage-specific differentiation arrest. Hence, TAL and/or LMO deregulation is typical of T-ALL with a mature phenotype (sCD3 positive) that of TLX1, NKX2-1, or TLX3, of cortical T-ALL (CD1a positive); HOXA and MEF2C are instead over-expressed in subsets of Early T-cell Precursor (ETP; immature phenotype) and early T-ALL. Among immature T-ALL, genomic alterations, that cause BCL11B transcriptional deregulation, identify a specific genetic subgroup. Although comprehensive cytogenetic and molecular studies have shed light on the genetic background of T-ALL, biomarkers are not currently adopted in the diagnostic workup of T-ALL, and only a limited number of studies have assessed their clinical implications. In this review, we will focus on recurrent T-ALL abnormalities that define specific leukemogenic pathways and on oncogenes/oncosuppressors that can serve as diagnostic biomarkers. Moreover, we will discuss how the complex genomic profile of T-ALL can be used to address and test innovative/targeted therapeutic options.

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A Tumor Suppressor Enhancer ofPTENin T-cell Development and Leukemia

Abstract: Long-range oncogenic enhancers play an important role in cancer. Yet, whether similar regulation of tumor suppressor genes is relevant remains unclear. Loss of expression of PTEN is associated with the pathogenesis of various cancers, including T-cell leukemia

Cited by 18 publications

References 87 publications

A therapeutically targetable NOTCH1-SIRT1-KAT7 axis in T-cell Leukemia

A therapeutically targetable NOTCH1-SIRT1-KAT7 axis in T-cell Leukemia

In vivo interrogation of regulatory genomes reveals extensive quasi-insufficiency in cancer evolution

T-Cell Acute Lymphoblastic Leukemia: Biomarkers and Their Clinical Usefulness

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