The Physiopathology of T- Cell Acute Lymphoblastic Leukemia: Focus on Molecular Aspects

Fattizzo, Bruno; Rosa, Joaquín M. Campos; Giannotta, Juri Alessandro; Baldini, Luca; Fracchiolla, Nicola Stefano

doi:10.3389/fonc.2020.00273

Cited by 59 publications

(59 citation statements)

References 110 publications

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“…In T-ALL cases (Figure 3), we found many more missense/INDEL mutations in the HD domain than expected by chance (n = 768 out of 843) (35), which was consistent with previous studies demonstrating that missense and in-frame mutations in this domain activate NOTCH1 signaling [25,32,46]. Because a disproportionally large number of observed NOTCH1 mutations in T-ALL cases mapped to the HD domain (92%), it skewed the estimated number of mutations expected to be randomly distributed over the remaining regions.…”

Section: Structural Characterization Of Notch1 Mutationssupporting

confidence: 92%

“…The C-terminal PEST domain in NOTCH is a target for binding F-box proteins (e.g., FBXW7), components of a ubiquitin protein ligase complex that degrades activated ICN to temporally limit signaling. Certain leukemias arise with inactivating FBXW7 mutations in the cancer cells that complement NOTCH1 activation by preventing ICN1 degradation [ 32 ].…”

Section: Notch1 Encodes For a Conserved Receptomentioning

confidence: 99%

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NOTCH1 Signaling in Head and Neck Squamous Cell Carcinoma

Shah

Huang

et al. 2020

Cells

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Biomarker-driven targeted therapies are lacking for head and neck squamous cell carcinoma (HNSCC), which is common and lethal. Efforts to develop such therapies are hindered by a genomic landscape dominated by the loss of tumor suppressor function, including NOTCH1 that is frequently mutated in HNSCC. Clearer understanding of NOTCH1 signaling in HNSCCs is crucial to clinically targeting this pathway. Structural characterization of NOTCH1 mutations in HNSCC demonstrates that most are predicted to cause loss of function, in agreement with NOTCH1’s role as a tumor suppressor in this cancer. Experimental manipulation of NOTCH1 signaling in HNSCC cell lines harboring either mutant or wild-type NOTCH1 further supports a tumor suppressor function. Additionally, the loss of NOTCH1 signaling can drive HNSCC tumorigenesis and clinical aggressiveness. Our recent data suggest that NOTCH1 controls genes involved in early differentiation that could have different phenotypic consequences depending on the cancer’s genetic background, including acquisition of pseudo-stem cell-like properties. The presence of NOTCH1 mutations may predict response to treatment with an immune checkpoint or phosphatidylinositol 3-kinase inhibitors. The latter is being tested in a clinical trial, and if validated, it may lead to the development of the first biomarker-driven targeted therapy for HNSCC.

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Section: Structural Characterization Of Notch1 Mutationssupporting

confidence: 92%

Section: Notch1 Encodes For a Conserved Receptomentioning

confidence: 99%

NOTCH1 Signaling in Head and Neck Squamous Cell Carcinoma

Shah

Huang

et al. 2020

Cells

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“…Excessive expression of MYC may also be due to gain-of-function NOTCH1 mutations [ 45 ]. It is worth mentioning that changes in the PI3K/AKT path often leads to increased expression of MYC [ 46 ]. In patients with abnormal MYC, some genetic abnormalities were found with higher frequency than in other patients.…”

Section: Genetic Profile Of T-allmentioning

confidence: 99%

Comprehensive Overview of Gene Rearrangements in Childhood T-Cell Acute Lymphoblastic Leukaemia

Mroczek

Zawitkowska

Kowalczyk

et al. 2021

IJMS

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Acute lymphoblastic leukaemia (ALL) is a relevant form of childhood neoplasm, as it accounts for over 80% of all leukaemia cases. T-cell ALL constitutes a genetically heterogeneous cancer derived from T-lymphoid progenitors. The diagnosis of T-ALL is based on morphologic, immunophenotypic, cytogenetic, and molecular features, thus the results are used for patient stratification. Due to the expression of surface and intracellular antigens, several subtypes of T-ALL can be distinguished. Although the aetiology of T-ALL remains unclear, a wide spectrum of rearrangements and mutations affecting crucial signalling pathways has been described so far. Due to intensive chemotherapy regimens and supportive care, overall cure rates of more than 80% in paediatric T-ALL patients have been accomplished. However, improved knowledge of the mechanisms of relapse, drug resistance, and determination of risk factors are crucial for patients in the high-risk group. Even though some residual disease studies have allowed the optimization of therapy, the identification of novel diagnostic and prognostic markers is required to individualize therapy. The following review summarizes our current knowledge about genetic abnormalities in paediatric patients with T-ALL. As molecular biology techniques provide insights into the biology of cancer, our study focuses on new potential therapeutic targets and predictive factors which may improve the outcome of young patients with T-ALL.

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“…Mutations in JAK1 and JAK3, as well as other rare mutations in JAK2, have been associated with T-cell acute lymphoblastic leukemia (T-ALL) [ 67 , 68 ]. Similarly, JAK1 mutations were found in 9% cases of hepatocellular carcinoma; in particular, the S703I mutation is likely responsible for the loss of JAK1 auto-inhibition ability [ 69 , 70 , 71 ].…”

Section: The Rise Of Jak Inhibitorsmentioning

confidence: 99%

Inside Perspective of the Synthetic and Computational Toolbox of JAK Inhibitors: Recent Updates

et al. 2020

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The mechanisms of inflammation and cancer are intertwined by complex networks of signaling pathways. Dysregulations in the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway underlie several pathogenic conditions related to chronic inflammatory states, autoimmune diseases and cancer. Historically, the potential application of JAK inhibition has been thoroughly explored, thus triggering an escalation of favorable results in this field. So far, five JAK inhibitors have been approved by the Food and Drug Administration (FDA) for the treatment of different diseases. Considering the complexity of JAK-depending processes and their involvement in multiple disorders, JAK inhibitors are the perfect candidates for drug repurposing and for the assessment of multitarget strategies. Herein we reviewed the recent progress concerning JAK inhibition, including the innovations provided by the release of JAKs crystal structures and the improvement of synthetic strategies aimed to simplify of the industrial scale-up.

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The Physiopathology of T- Cell Acute Lymphoblastic Leukemia: Focus on Molecular Aspects

Cited by 59 publications

References 110 publications

NOTCH1 Signaling in Head and Neck Squamous Cell Carcinoma

NOTCH1 Signaling in Head and Neck Squamous Cell Carcinoma

Comprehensive Overview of Gene Rearrangements in Childhood T-Cell Acute Lymphoblastic Leukaemia

Inside Perspective of the Synthetic and Computational Toolbox of JAK Inhibitors: Recent Updates

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