HES1 and HES4 have non-redundant roles downstream of Notch during early human T-cell development

Decker, Matthias De; Lavaert, Marieke; Roels, Juliette; Tilleman, Laurentijn; Vandekerckhove, Bart; Leclercq, Georges; Nieuwerburgh, Filip Van; Vlierberghe, Pieter Van; Taghon, Tom

doi:10.3324/haematol.2019.226126

Cited by 28 publications

(23 citation statements)

References 55 publications

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“…Thus, copy number gains of HES4 may be a further mechanism for enforced NOTCH pathway activation in OAML. Although CEBP family members are mainly known for their function in myeloid cells, there are indications that CEBPB and CEBPD may have roles in B lineage malignancies [21][22][23].…”

Section: Discussionmentioning

confidence: 99%

“…HES4 showed gains in four of the cases. HES4 is a downstream target and effector of NOTCH activity [21]. CEBPB, which showed gains in four OAML, functions as transcription factor in myeloid cells, but it also has a pathogenetic role in multiple myelomas, and positively regulates BCL2 in B cells [22,23].…”

Section: Analysis Of Wgs Data For Cnvs Chromosomal Translocations Amentioning

confidence: 99%

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Identifying Genetic Lesions in Ocular Adnexal Extranodal Marginal Zone Lymphomas of the MALT Subtype by Whole Genome, Whole Exome and Targeted Sequencing

Johansson

Klein-Hitpaß

Budeus

et al. 2020

Cancers

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The pathogenesis of ocular adnexal marginal zone lymphomas of mucosa-associated lymphatic tissue-type (OAML) is not fully understood. We performed whole genome sequencing (WGS) and/or whole exome sequencing (WES) for 13 cases of OAML and sequenced 38 genes selected from this analysis in a large cohort of 82 OAML. Besides confirmation of frequent mutations in the genes transducin beta like 1 X-linked receptor 1 (TBL1XR1) and cAMP response element binding protein (CREBBP), we newly identifed JAK3 as a frequently mutated gene in OAML (11% of cases). In our retrospective cohort, JAK3 mutant cases had a shorter progression-free survival compared with unmutated cases. Other newly identified genes recurrently mutated in 5–10% of cases included members of the collagen family (collagen type XII alpha 1/2 (COL12A1, COL1A2)) and DOCK8. Evaluation of the WGS data of six OAML did not reveal translocations or a current infection of the lymphoma cells by viruses. Evaluation of the WGS data for copy number aberrations confirmed frequent loss of TNFAIP3, and revealed recurrent gains of the NOTCH target HES4, and of members of the CEBP transcription factor family. Overall, we identified several novel genes recurrently affected by point mutations or copy number alterations, but our study also indicated that the landscape of frequently (>10% of cases) mutated protein-coding genes in OAML is now largely known.

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Section: Discussionmentioning

confidence: 99%

Section: Analysis Of Wgs Data For Cnvs Chromosomal Translocations Amentioning

confidence: 99%

Identifying Genetic Lesions in Ocular Adnexal Extranodal Marginal Zone Lymphomas of the MALT Subtype by Whole Genome, Whole Exome and Targeted Sequencing

Johansson

Klein-Hitpaß

Budeus

et al. 2020

Cancers

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“…Several studies showed that DNA methylation can alter the binding of CTCF to influence the 3D architecture of the genome (38)(39)(40). Therefore, we compared the genes downregulated by Decitabine in both PDX and T-ALL cell lines with gene expression in CTCF depleted acute leukemia (41).…”

Section: Cluster a Cpg Island Methylation Defines The Proliferative Hmentioning

confidence: 99%

Aging of Preleukemic Thymocytes Drives CpG Island Hypermethylation in T-cell Acute Lymphoblastic Leukemia

Roels

Thénoz

Szarzyńska

et al. 2020

Blood Cancer Discovery

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Cancer cells display DNA hypermethylation at specific CpG islands in comparison to their normal healthy counterparts, but the mechanism that drives this so-called CpG island methylator phenotype (CIMP) remains poorly understood. Here, we show that CpG island methylation in human T-cell acute lymphoblastic leukemia (T-ALL) mainly occurs at promoters of Polycomb Repressor Complex 2 (PRC2) target genes that are not expressed in normal or malignant T-cells and which display a reciprocal association with H3K27me3 binding. In addition, we revealed that this aberrant methylation profile reflects the epigenetic history of TALL and is established already in pre-leukemic, self-renewing thymocytes that precede TALL development. Finally, we unexpectedly uncover that this age-related CpG island hypermethylation signature in TALL is completely resistant to the FDA-approved hypomethylating agent Decitabine. Altogether, we here provide conceptual evidence for the involvement of a pre-leukemic phase characterized by self-renewing thymocytes in the pathogenesis of human TALL .

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“…For both genes, these types of mutations cause a gain of function, as the inhibitory C-terminal PEST domains are removed or otherwise inactivated. Copy number gains in the NOTCH target HES4 may be a further mechanism of enforced NOTCH pathway activity in OAMZL [ 51 , 100 ].…”

Section: Etiology and Pathogenesismentioning

confidence: 99%

The Biology of Ocular Adnexal Marginal Zone Lymphomas

Johansson

Eckstein

Küppers

2022

Cancers

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This review focuses on the biology of ocular adnexal marginal zone B-cell lymphomas of the mucosa-associated lymphatic tissue (MALT) (OAMZL) subtype. The ocular adnexa includes all structures and tissues within the orbit except for the eye bulb. In the region of the ocular adnexa, MALT lymphomas represent the most common subtype of lymphoma, accounting for around 8% of all non-Hodgkin lymphomas. These lymphomas are often preceded by inflammatory precursor lesions. Either autoantigens or infectious antigens may lead to disease development by functioning as continuous antigenic triggers. This triggering leads to a constitutive activation of the NF-κB signaling pathway. The role of antigenic stimulation in the pathogenesis of OAMZL is supported by the detection of somatic mutations (partially with further intraclonal diversity) in their rearranged immunoglobulin V genes; hence, their derivation from germinal-center-experienced B cells, by a restricted IGHV gene usage, and the validation of autoreactivity of the antibodies in selected cases. In the established lymphomas, NF-κB activity is further enforced by mutations in various genes regulating NF-κB activity (e.g., TNFAIP3, MYD88), as well as recurrent chromosomal translocations affecting NF-κB pathway components in a subset of cases. Further pathogenetic mechanisms include mutations in genes of the NOTCH pathway, and of epigenetic regulators. While gene expression and sequencing studies are available, the role of differential methylation of lymphoma cells, the role of micro-RNAs, and the contribution of the microenvironment remain largely unexplored.

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HES1 and HES4 have non-redundant roles downstream of Notch during early human T-cell development

Cited by 28 publications

References 55 publications

Identifying Genetic Lesions in Ocular Adnexal Extranodal Marginal Zone Lymphomas of the MALT Subtype by Whole Genome, Whole Exome and Targeted Sequencing

Identifying Genetic Lesions in Ocular Adnexal Extranodal Marginal Zone Lymphomas of the MALT Subtype by Whole Genome, Whole Exome and Targeted Sequencing

Aging of Preleukemic Thymocytes Drives CpG Island Hypermethylation in T-cell Acute Lymphoblastic Leukemia

The Biology of Ocular Adnexal Marginal Zone Lymphomas

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