TET2 in Normal and Malignant Hematopoiesis

Bowman, Robert L.; Levine, Ross L.

doi:10.1101/cshperspect.a026518

Cited by 79 publications

(64 citation statements)

References 72 publications

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“…142,143 Integration site analysis revealed that the virus disrupted the function of TET2, a gene involved in epigenetic modification which is also associated with myeloid malignancies. 144 This finding highlights that viral integration-induced gene disruption remains a clinical possibility, albeit a rare one. Second, integrating viruses leave the endogenous TCR intact, providing a "sink" for limiting intracellular signal transduction molecules, including CD3 and Lck.…”

Section: Non-viral Tcr Integration Strategiesmentioning

confidence: 91%

T cell receptor‐based cancer immunotherapy: Emerging efficacy and pathways of resistance

Chandran

Klebanoff

2019

Immunological Reviews

237

185

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Adoptive cell transfer (ACT) using chimeric antigen receptor (CAR)‐modified T cells can induce durable remissions in patients with refractory B‐lymphoid cancers. By contrast, results applying CAR‐modified T cells to solid malignancies have been comparatively modest. Alternative strategies to redirect T cell specificity and cytolytic function are therefore necessary if ACT is to serve a greater role in human cancer treatments. T cell receptors (TCRs) are antigen recognition structures physiologically expressed by all T cells that have complementary, and in some cases superior, properties to CARs. Unlike CARs, TCRs confer recognition to epitopes derived from proteins residing within any subcellular compartment, including the membrane, cytoplasm and nucleus. This enables TCRs to detect a broad universe of targets, such as neoantigens, cancer germline antigens, and viral oncoproteins. Moreover, because TCRs have evolved to efficiently detect and amplify antigenic signals, these receptors respond to epitope densities many fold smaller than required for CAR‐signaling. Herein, we summarize recent clinical data demonstrating that TCR‐based immunotherapies can mediate regression of solid malignancies, including immune‐checkpoint inhibitor refractory cancers. These trials simultaneously highlight emerging mechanisms of TCR resistance. We conclude by discussing how TCR‐based immunotherapies can achieve broader dissemination through innovations in cell manufacturing and non‐viral genome integration techniques.

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Section: Non-viral Tcr Integration Strategiesmentioning

confidence: 91%

T cell receptor‐based cancer immunotherapy: Emerging efficacy and pathways of resistance

Chandran

Klebanoff

2019

Immunological Reviews

237

185

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“…EZH2 is affected by somatic gainof-function mutations in 30% of GCB-DLBCL and FL patients. 118 Gene promoter 5mC is linked to transcriptional repression, whereas 5hmC is a transcriptional activation mark at gene enhancers ( Figure 2). Y641 mutant EZH2 yields more efficient H3K27 trimethylation but loss of H3K27 monomethylation activity.…”

Section: Core Epi G Ene Tic Mechanis Ms Driving G C-derived Lymphommentioning

confidence: 99%

“…39,57 TET2 is an alpha-ketoglurate (aKG)-dependent dioxygenase that converts 5'methylcytosine (5mC) into 5'hydroxymethylcytosine (5hmC). 118 Gene promoter 5mC is linked to transcriptional repression, whereas 5hmC is a transcriptional activation mark at gene enhancers ( Figure 2). 119 Loss of Tet2 results in GC hyperplasia in mice and failure to undergo class-switch recombination and plasma cell differentiation, ultimately leading to the development of B-cell lymphomas.…”

Section: Core Epi G Ene Tic Mechanis Ms Driving G C-derived Lymphommentioning

confidence: 99%

Germinal center‐derived lymphomas: The darkest side of humoral immunity

Mlynarczyk

Fontán

Melnick

2019

Immunological Reviews

133

142

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Summary One of the unusual features of germinal center (GC) B cells is that they manifest many hallmarks of cancer cells. Accordingly, most B‐cell neoplasms originate from the GC reaction, and characteristically display abundant point mutations, structural genomic lesions, and clonal diversity from the genetic and epigenetic standpoints. The dominant biological theme of GC‐derived lymphomas is mutation of genes involved in epigenetic regulation and immune receptor signaling, which come into play at critical transitional stages of the GC reaction. Hence, mechanistic studies of these mutations reveal fundamental insight into the biology of the normal and malignant GC B cell. The BCL6 transcription factor plays a central role in establishing the GC phenotype in B cells, and most lymphomas are dependent on BCL6 to maintain survival, proliferation, and perhaps immune evasion. Many lymphoma mutations have the commonality of enhancing the oncogenic functions of BCL6, or overcoming some of its tumor suppressive effects. Herein, we discuss how unique features of the GC reaction create vulnerabilities that select for particular lymphoma mutations. We examine the interplay between epigenetic programming, metabolism, signaling, and immune regulatory mechanisms in lymphoma, and discuss how these are leading to novel precision therapy strategies to treat lymphoma patients.

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“…Mutations in TET2, ASXL1, and SRSF2 tended to co-occur with mutations in at least one other gene with 37 of the 42 TET2 mutations occurring in samples with additional mutations, in keeping with its role as a driver of myeloid cancers. 36 The most commonly co-occurring mutation pair was between JAK2 and TET2 (Figure 2C; Tables S8 and S9).…”

Section: Variant Assessment In Patient Samplesmentioning

confidence: 99%

Implementation of an NGS‐based sequencing and gene fusion panel for clinical screening of patients with suspected hematologic malignancies

Levy

Santos

Kerkhof

et al. 2019

European J of Haematology

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Objectives:The diagnosis of hematologic malignancies integrates multiple diagnostic and clinical disciplines. Historically, targeted (single-analyte) genetic testing has been used as reflex to initial prescreening by other diagnostic modalities including flow cytometry, anatomic pathology, and clinical cytogenetics. Given the wide range of mutations associated with hematologic malignancies a DNA/RNA-based NGS panel can provide a more effective and economical approach to comprehensive testing of patients as an initial, tier-1 screen. | 179 LEVY Et aL.Methods: Using a cohort of 380 patients, we performed clinical validation of a gene panel designed to assess 40 genes (DNA), and 29 fusion driver genes with over 600 gene fusion partners (RNA), including sample exchange data across three clinical laboratories, and correlation with cytogenetic testing results. Results:The clinical validation of this technology demonstrated that its accuracy, sensitivity, and specificity are comparable to the majority of targeted single-gene approaches, while assessment of the initial patient cohort data demonstrated a high diagnostic yield of 50.5%.Conclusions: Implementation of a tier-1 NGS-based protocol for gene panel screening provides a comprehensive alternative to targeted molecular testing in patients with suspected hematologic malignancies, with increased diagnostic yield, scalability, reproducibility, and cost effectiveness, making it ideally suited for implementation in clinical laboratories.

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TET2 in Normal and Malignant Hematopoiesis

Cited by 79 publications

References 72 publications

T cell receptor‐based cancer immunotherapy: Emerging efficacy and pathways of resistance

T cell receptor‐based cancer immunotherapy: Emerging efficacy and pathways of resistance

Germinal center‐derived lymphomas: The darkest side of humoral immunity

Implementation of an NGS‐based sequencing and gene fusion panel for clinical screening of patients with suspected hematologic malignancies

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