Deletions of the long arm of chromosome 5 define subgroups of T-cell acute lymphoblastic leukemia

Starza, Roberta La; Barba, Gianluca; Demeyer, Sofie; Pierini, Valentina; Giacomo, Danika Di; Gianfelici, Valentina; Schwab, Claire; Matteucci, Caterina; Vicente, Carmen; Cools, Jan; Messina, Monica; Crescenzi, Barbara; Chiaretti, Sabina; Foà, Robin; Basso, Giuseppe; Harrison, Christine J.; Mecucci, Cristina

doi:10.3324/haematol.2016.143875

Cited by 18 publications

(17 citation statements)

References 51 publications

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“…In addition, recurrent 5q deletions result in deletion of the NR3C1 locus, encoding for the glucocorticoid receptor (GCR; refs. 22,23). Interestingly, recent evidence demonstrated that reduced GCR expression can induce steroid resistance in T-ALL (12).…”

Section: Oncogenic Drivers and T-all Subtypesmentioning

confidence: 99%

T-cell Acute Lymphoblastic Leukemia: A Roadmap to Targeted Therapies

Cordó

Zwet

Canté-Barrett

et al. 2021

Blood Cancer Discovery

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T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy characterized by aberrant proliferation of immature thymocytes. Despite an overall survival of 80% in the pediatric setting, 20% of patients with TALL ultimately die from relapsed or refractory disease. Therefore, there is an urgent need for novel therapies. Molecular genetic analyses and sequencing studies have led to the identification of recurrent TALL genetic drivers. This review summarizes the main genetic drivers and targetable lesions of TALL and gives a comprehensive overview of the novel treatments for patients with TALL that are currently under clinical investigation or that are emerging from preclinical research. Significance: TALL is driven by oncogenic transcription factors that act along with secondary acquired mutations. These lesions, together with active signaling pathways, may be targeted by therapeutic agents. Bridging research and clinical practice can accelerate the testing of novel treatments in clinical trials, offering an opportunity for patients with poor outcome.

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Section: Oncogenic Drivers and T-all Subtypesmentioning

confidence: 99%

T-cell Acute Lymphoblastic Leukemia: A Roadmap to Targeted Therapies

Cordó

Zwet

Canté-Barrett

et al. 2021

Blood Cancer Discovery

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“…TYK2 activation is then responsible for the activation of several downstream effectors, such as STAT proteins, thus promoting cell survival [59,60]. Another novel genomic rearrangement, resulting in the chimeric protein NPM1-HAUS1 (Augmin-Like Complex Subunit 1), has been identified in AML patients [61], while an interstitial deletion of 5q associated with NPM1 haploinsufficiency has been observed in myelodysplastic syndromes (MDS) [62] but also found in AML [63] and in T-cell acute lymphoblastic leukemia (T-ALL) [64].…”

Section: Role In Cancermentioning

confidence: 99%

Nucleophosmin in Its Interaction with Ligands

Cela

Matteo

Federici

2020

IJMS

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Nucleophosmin (NPM1) is a mainly nucleolar protein that shuttles between nucleoli, nucleoplasm and cytoplasm to fulfill its many functions. It is a chaperone of both nucleic acids and proteins and plays a role in cell cycle control, centrosome duplication, ribosome maturation and export, as well as the cellular response to a variety of stress stimuli. NPM1 is a hub protein in nucleoli where it contributes to nucleolar organization through heterotypic and homotypic interactions. Furthermore, several alterations, including overexpression, chromosomal translocations and mutations are present in solid and hematological cancers. Recently, novel germline mutations that cause dyskeratosis congenita have also been described. This review focuses on NPM1 interactions and inhibition. Indeed, the list of NPM1 binding partners is ever-growing and, in recent years, many studies contributed to clarifying the structural basis for NPM1 recognition of both nucleic acids and several proteins. Intriguingly, a number of natural and synthetic ligands that interfere with NPM1 interactions have also been reported. The possible role of NPM1 inhibitors in the treatment of multiple cancers and other pathologies is emerging as a new therapeutic strategy.

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“…Other studies have confirmed CNOT3 mutations in T-ALL and have also identified mutations in CNOT1 and CNOT2 [ 14 – 16 ]. Furthermore, T-ALL patients with HOXA-rearrangements and terminal 5q deletions show CNOT6 downregulation and high incidence of CNOT3 mutations [ 17 ]. These data suggest that the CCR4-NOT complex is involved in cancer, although it remains unclear how it is contributing to tumor development.…”

Section: Introductionmentioning

confidence: 99%

The CCR4-NOT complex is a tumor suppressor in Drosophila melanogaster eye cancer models

et al. 2018

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BackgroundThe CNOT3 protein is a subunit of the CCR4-NOT complex, which is involved in mRNA degradation. We recently identified CNOT3 loss-of-function mutations in patients with T-cell acute lymphoblastic leukemia (T-ALL).MethodsHere, we use different Drosophila melanogaster eye cancer models to study the potential tumor suppressor function of Not3, the CNOT3 orthologue, and other members of the CCR4-NOT complex.ResultsOur data show that knockdown of Not3, the structural components Not1/Not2, and the deadenylases twin/Pop2 all result in increased tumor formation. In addition, overexpression of Not3 could reduce tumor formation. Not3 downregulation has a mild but broad effect on gene expression and leads to increased levels of genes involved in DNA replication and ribosome biogenesis. CycB upregulation also contributes to the Not3 tumor phenotype. Similar findings were obtained in human T-ALL cell lines, pointing out the conserved function of Not3.ConclusionsTogether, our data establish a critical role for Not3 and the entire CCR4-NOT complex as tumor suppressor.Electronic supplementary materialThe online version of this article (10.1186/s13045-018-0650-0) contains supplementary material, which is available to authorized users.

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Deletions of the long arm of chromosome 5 define subgroups of T-cell acute lymphoblastic leukemia

Cited by 18 publications

References 51 publications

T-cell Acute Lymphoblastic Leukemia: A Roadmap to Targeted Therapies

T-cell Acute Lymphoblastic Leukemia: A Roadmap to Targeted Therapies

Nucleophosmin in Its Interaction with Ligands

The CCR4-NOT complex is a tumor suppressor in Drosophila melanogaster eye cancer models

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