The Transcriptional Roles of ALK Fusion Proteins in Tumorigenesis

Ducray, Stephen P.; Natarajan, Karthikraj; Garland, Gavin D.; Turner, Suzanne D.; Egger, Gerda

doi:10.3390/cancers11081074

Cited by 70 publications

(55 citation statements)

References 165 publications

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“…The ALK protein has been identified as a driver oncogene in diverse cancers, based on its overexpression following genetic translocation, amplification or mutation (81)(82)(83).…”

Section: Discussionmentioning

confidence: 99%

Requirement of DNMT1 to orchestrate epigenomic reprogramming during NPM-ALK driven T cell lymphomagenesis

Redl

Sheibani-Tezerji

Hamminger

et al. 2020

Preprint

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Phone: +43 1 40400 22390The authors declare no potential conflicts of interest.Word count: Abstract 150, Statement of significance 52, Main text 4881, Methods 2072. ABSTRACTMalignant transformation depends on genetic and epigenetic events that result in a burst of deregulated gene expression and chromatin changes. To dissect the sequence of events in this process, we used a T cell-specific lymphoma model based on the human oncogenic NPM-ALK translocation. We find that transformation of T cells shifts thymic cell populations to an undifferentiated immunophenotype, which occurs only after a period of latency, accompanied by induction of the MYC-NOTCH1 axis and deregulation of key epigenetic enzymes. We discover aberrant DNA methylation patterns, overlapping with regulatory regions, plus a high degree of epigenetic heterogeneity between individual tumors. In addition, ALK positive tumors show a loss of collaborative methylation patterns of neighboring CpG sites. Notably, deletion of the maintenance DNA methyltransferase DNMT1 completely abrogates lymphomagenesis in this model, despite oncogenic signaling through NPM-ALK, suggesting that faithful maintenance of tumor-specific methylation through DNMT1 is essential for sustained proliferation and tumorigenesis. STATEMENT OF SIGNIFICANCEEpigenetic alterations are causally involved in tumorigenesis. Here we show that induction of a single human oncogene in murine T cells induces specific deregulation of epigenetic enzymes resulting in epigenomic alterations similar to human tumors. Our findings are of broader implication to understand how epigenomic processes are shaped by oncogene induced transformation.

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“…The ALK protein has been identified as a driver oncogene in diverse cancers, based on its overexpression following genetic translocation, amplification or mutation (81)(82)(83).…”

Section: Discussionmentioning

confidence: 99%

Requirement of DNMT1 to orchestrate epigenomic reprogramming during NPM-ALK driven T cell lymphomagenesis

Redl

Sheibani-Tezerji

Hamminger

et al. 2020

Preprint

Self Cite

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“…These mutations that impair receptor intracellular trafficking and degradation/turnover can help to prolong the propagation of the signal and to locate receptors at specific membrane sites, stimulating cell motility and the formation of invadopodia [ 73 , 74 ]. Another example is the EML4-ALK fusion gene, resulting from the inversion of the short arm of the chromosome 2, gives rise to the expression of a chimeric protein with the tyrosine kinase domain constitutively activated [ 75 ]. Definitely, overactivation of the TKR represents a key pathogenic factor in the development of cancer.…”

Section: Roles Of Tkrs In Tumor Biologymentioning

confidence: 99%

Tyrosine Kinase Receptors in Oncology

Esteban-Villarrubia

Castillo

Pozas

et al. 2020

IJMS

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Tyrosine kinase receptors (TKR) comprise more than 60 molecules that play an essential role in the molecular pathways, leading to cell survival and differentiation. Consequently, genetic alterations of TKRs may lead to tumorigenesis and, therefore, cancer development. The discovery and improvement of tyrosine kinase inhibitors (TKI) against TKRs have entailed an important step in the knowledge-expansion of tumor physiopathology as well as an improvement in the cancer treatment based on molecular alterations over many tumor types. The purpose of this review is to provide a comprehensive review of the different families of TKRs and their role in the expansion of tumor cells and how TKIs can stop these pathways to tumorigenesis, in combination or not with other therapies. The increasing growth of this landscape is driving us to strengthen the development of precision oncology with clinical trials based on molecular-based therapy over a histology-based one, with promising preliminary results.

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“…Although JAK3 is phosphorylated, its binding is not essential for STAT3 activity. NPM-ALK fusion transcripts could activate STAT3 directly (52). This activation is important, as STAT3 is integral to cell survival by controlling the transcription of numerous apoptosisregulating proteins, such as cyclin D1, Bcl-X, Bcl-XL, and c-Myc (53).…”

Section: Alk + Alclmentioning

confidence: 99%

Genomics of Peripheral T-Cell Lymphoma and Its Implications for Personalized Medicine

et al. 2020

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Peripheral T-cell lymphoma (PTCL) is a rare, heterogenous group of mature T-cell neoplasms that comprise 10-15% of non-Hodgkin lymphoma cases in the United States. All subtypes of PTCL, except for ALK + anaplastic T-cell lymphoma, are associated with poor prognosis, with median overall survival (OS) rates of 1-3 years. The diagnosis of PTCL is mainly based on clinical presentation, morphologic features, and immunophenotypes. Recent advances in genome sequencing and gene expression profiling have given new insights into the pathogenesis and molecular biology of PTCL. An enhanced understanding of its genomic landscape holds the promise of refining the diagnosis, prognosis, and management of PTCL. In this review, we examine recently discovered genetic abnormalities identified by molecular profiling in 3 of the most common types of PTCL: RHOA G17V and epigenetic regulator mutations in angioimmunoblastic T-cell lymphoma, ALK expression and JAK/STAT3 pathway mutations in anaplastic T-cell lymphoma, and T-follicular helper phenotype and GATA3/TBX21 expression in PTCL-not otherwise specified. We also discuss the implications of these abnormalities for clinical practice, new/potential targeted therapies, and the role of personalized medicine in the management of PTCL.

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The Transcriptional Roles of ALK Fusion Proteins in Tumorigenesis

Cited by 70 publications

References 165 publications

Requirement of DNMT1 to orchestrate epigenomic reprogramming during NPM-ALK driven T cell lymphomagenesis

Requirement of DNMT1 to orchestrate epigenomic reprogramming during NPM-ALK driven T cell lymphomagenesis

Tyrosine Kinase Receptors in Oncology

Genomics of Peripheral T-Cell Lymphoma and Its Implications for Personalized Medicine

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