Models for mature T-cell lymphomas—A critical appraisal of experimental systems and their contribution to current T-cell tumorigenic concepts

Warner, Kathrin; Crispatzu, Giuliano; Al-Ghaili, N; Weit, Nicole; Florou, Vaia; You, M. James; Newrzela, Sebastian; Herling, Marco

doi:10.1016/j.critrevonc.2013.07.014

Cited by 17 publications

(14 citation statements)

References 104 publications

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“…Another notable feature of the cancers in Pole P286R/+ mice was their aggressive clinical features and histology. For example, the T cell lymphomas were large, and many were widely disseminated and in the leukemic phase with bone marrow infiltration, a markedly aggressive phenotype for a mouse model of T cell lymphoma (37,38). Also, few benign tumors were identified, with most tumors exhibiting striking tissue invasion and thus representing obvious malignancies.…”

Section: Discussionmentioning

confidence: 99%

Polymerase-mediated ultramutagenesis in mice produces diverse cancers with high mutational load

Li¹,

Cuevas²,

Zhang³

et al. 2018

Journal of Clinical Investigation

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Mutations underlie all cancers, and their identification and study are the foundation of cancer biology. We describe what we believe to be a novel approach to mutagenesis and cancer studies based on the DNA polymerase ε (POLE) ultramutator phenotype recently described in human cancers, in which a single amino acid substitution (most commonly P286R) in the proofreading domain results in error-prone DNA replication. We engineered a conditional PoleP286R allele in mice. PoleP286R/+ embryonic fibroblasts exhibited a striking mutator phenotype and immortalized more efficiently. PoleP286R/+ mice were born at Mendelian ratios but rapidly developed lethal cancers of diverse lineages, yielding the most cancer-prone monoallelic model described to date, to our knowledge. Comprehensive whole-genome sequencing analyses showed that the cancers were driven by high base substitution rates in the range of human cancers, overcoming a major limitation of previous murine cancer models. These data establish polymerase-mediated ultramutagenesis as an efficient in vivo approach for the generation of diverse animal cancer models that recapitulate the high mutational loads inherent to human cancers.

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Section: Discussionmentioning

confidence: 99%

Polymerase-mediated ultramutagenesis in mice produces diverse cancers with high mutational load

Li¹,

Cuevas²,

Zhang³

et al. 2018

Journal of Clinical Investigation

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“…Regardless, in no cases has a PTCL presented in mice expressing NPM-ALK in a transgenic context even though the CD4 promoter also drives expression in mature T cells (the CD4 promoter construct used to generate these mice lacks silencing elements that would normally supress expression in early thymocytes [ 86 ]). The consequences of driving NPM-ALK expression exclusively in mature T cells are yet to be explored, largely due to the current lack of any peripheral T-cell-specific promoters for use in the transgenic context (reviewed in [ 87 ]).…”

Section: An Immature Origin For a Mature T-cell Lymphoma?mentioning

confidence: 99%

Challenging perspectives on the cellular origins of lymphoma

et al. 2016

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Both B and T lymphocytes have signature traits that set them apart from other cell types. They actively and repeatedly rearrange their DNA in order to produce a unique and functional antigen receptor, they have potential for massive clonal expansion upon encountering antigen via this receptor or its precursor, and they have the capacity to be extremely long lived as ‘memory’ cells. All three of these traits are fundamental to their ability to function as the adaptive immune response to infectious agents, but concurrently render these cells vulnerable to transformation. Thus, it is classically considered that lymphomas arise at a relatively late stage in a lymphocyte's development during the process of modifying diversity within antigen receptors, and when the cell is capable of responding to stimulus via its receptor. Attempts to understand the aetiology of lymphoma have reinforced this notion, as the most notable advances to date have shown chronic stimulation of the antigen receptor by infectious agents or self-antigens to be key drivers of these diseases. Despite this, there is still uncertainty about the cell of origin in some lymphomas, and increasing evidence that a subset arises in a more immature cell. Specifically, a recent study indicates that T-cell lymphoma, in particular nucleophosmin-anaplastic lymphoma kinase-driven anaplastic large cell lymphoma, may originate in T-cell progenitors in the thymus.

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“…Recently, kinase-targeted therapies and immunostimulatory antibodies or a combination of them have been successfully introduced into the treatment of melanoma [3-7]. From the pathogenetic point of view, melanoma is a complex disease that arises thorough activation of several crucial cell-signaling pathways [8,9].…”

Section: Introductionmentioning

confidence: 99%

Heterogeneous distribution of BRAF/NRAS mutations among Italian patients with advanced melanoma

Colombino

Lissia²,

Capone

et al. 2013

J Transl Med

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BackgroundPrevalence and distribution of pathogenetic mutations in BRAF and NRAS genes were evaluated in multiple melanoma lesions from patients with different geographical origin within the same Italian population.MethodsGenomic DNA from a total of 749 tumor samples (451 primary tumors and 298 metastases) in 513 consecutively-collected patients with advanced melanoma (AJCC stages III and IV) was screened for mutations in exon 15 of BRAF gene and, at lower extension (354/513; 69%), in the entire coding DNA of NRAS gene by automated direct sequencing. Among tissues, 236 paired samples of primary melanomas and synchronous or asynchronous metastases were included into the screening.ResultsOverall, mutations were detected in 49% primary melanomas and 51% metastases, for BRAF gene, and 15% primary tumors and 16% secondaries, for NRAS gene. A heterogeneous distribution of mutations in both genes was observed among the 451 primary melanomas according to patients’ geographical origin: 61% vs. 42% (p = 0.0372) BRAF-mutated patients and 2% vs. 21% (p < 0.0001) NRAS-mutated cases were observed in Sardinian and non-Sardinian populations, respectively. Consistency in BRAF/NRAS mutations among paired samples was high for lymph node (91%) and visceral metastases (92.5%), but significantly lower for brain (79%; p = 0.0227) and skin (71%; p = 0.0009) metastases.ConclusionsOur findings about the two main alterations occurring in the different tumor tissues from patients with advanced melanoma may be helpful in improving the management of such a disease.

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Models for mature T-cell lymphomas—A critical appraisal of experimental systems and their contribution to current T-cell tumorigenic concepts

Cited by 17 publications

References 104 publications

Polymerase-mediated ultramutagenesis in mice produces diverse cancers with high mutational load

Polymerase-mediated ultramutagenesis in mice produces diverse cancers with high mutational load

Challenging perspectives on the cellular origins of lymphoma

Heterogeneous distribution of BRAF/NRAS mutations among Italian patients with advanced melanoma

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