Kmt2c mutations enhance HSC self-renewal capacity and convey a selective advantage after chemotherapy

Chen, Ran; Okeyo-Owuor, Theresa; Patel, Riddhi; Casey, Emily; Cluster, Andrew; Yang, Wei; Magee, Jeffrey A.

doi:10.1016/j.celrep.2021.108751

Cited by 18 publications

(16 citation statements)

References 67 publications

(97 reference statements)

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“…The second highly expressed transcript is Kmt2c (lysine methyltransferase 2C), which is a tumour suppressor mutated or deleted in the peripheral T-cell lymphoma ( Watatani et al., 2019 ) and myelodysplastic syndrome (MDS) ( Chen et al., 2021 ). KMT2C upregulation modifies histones during NK-cell activation in humans, helping the rapid shift in the expression of particular genes above the baseline during the target recognition process ( Li et al., 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Rat and fish peripheral blood leukocytes respond distinctively to Anisakis pegreffii (Nematoda, Anisakidae) crude extract

Hrabar

Petrić

Cavallero³

et al. 2022

Front. Cell. Infect. Microbiol.

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Infective third-stage larvae (L3) of the marine nematode Anisakis pegreffii cause inflammation and clinical symptoms in humans, their accidental host, that subside and self-resolve in a couple of weeks after L3 die. To characterise the differences in an early immune response of a marine vs. terrestrial host, we stimulated peripheral blood leukocytes (PBLs) of fish (paratenic host) and rat (accidental, human-model host) with A. pegreffii crude extract and analysed PBL transcriptomes 1 and 12 h post-stimulation. Fish and rat PBLs differentially expressed 712 and 493 transcripts, respectively, between 1 and 12 h post-stimulation (false discovery rate, FDR <0.001, logFC >2). While there was a difference in the highest upregulated transcripts between two time-points, the same Gene Ontologies, biological processes (intracellular signal transduction, DNA-dependent transcription, and DNA-regulated regulation of transcription), and molecular functions (ATP and metal ion binding) were enriched in the two hosts, showing an incrementing dynamic between 1 and 12 h. This suggests that the two distinct hosts employ qualitatively different transcript cascades only to achieve the same effect, at least during an early innate immunity response. Activation of later immunity elements and/or a combination of other host’s intrinsic conditions may contribute to the death of L3 in the terrestrial host.

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Section: Discussionmentioning

confidence: 99%

Rat and fish peripheral blood leukocytes respond distinctively to Anisakis pegreffii (Nematoda, Anisakidae) crude extract

Hrabar

Petrić

Cavallero³

et al. 2022

Front. Cell. Infect. Microbiol.

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“…Cells were isolated, stained, analyzed and transplanted as previously described. 14, 20, 21 Flow cytometry antibodies and surface marker phenotypes are defined in Table S1, and representative gating strategies are shown in Figures S2, S4 and S5. Flow cytometry was performed on a BD FACSAria Fusion flow cytometer (BD Biosciences).…”

Section: Methodsmentioning

confidence: 99%

“…Cells were isolated, stained, analyzed and transplanted as previously described. 14,20,21 Flow cytometry antibodies and surface marker phenotypes are defined in Table S1…”

Section: Flow Cytometrymentioning

confidence: 99%

Basal type I interferon signaling has only modest effects on neonatal and juvenile hematopoiesis

Yang

Wang

et al. 2022

Preprint

Self Cite

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Type I interferon (IFN-1) regulates gene expression and hematopoiesis both during development and in response to inflammatory stress. We previously showed that during development, hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) induce IFN-1 target genes shortly before birth in mice. This coincides with the onset of a transition to adult hematopoiesis, and it drives expression of genes associated with antigen presentation. However, it is not clear whether perinatal IFN-1 modulates hematopoietic output, as has been observed in contexts of inflammation. We have characterized hematopoiesis at several different stages of blood formation, from HSCs to mature blood cells, and found that loss of the IFN-1 receptor (IFNAR1) leads to depletion of several phenotypic HSC and MPP subpopulations in neonatal and juvenile mice. Committed lymphoid and myeloid progenitor populations simultaneously expand. These changes had surprisingly little effect on production of more differentiated blood cells. Cellular Indexing of Transcriptomes and Epitopes by sequencing (CITE-seq) resolved the discrepancy between the extensive changes in progenitor numbers and modest changes in hematopoiesis, revealing stability in most MPP populations in Ifnar1-deficient neonates when the populations were identified based on gene expression rather than surface marker phenotype. Thus, basal IFN-1 signaling has only modest effects on hematopoiesis. Discordance between transcriptionally- and phenotypically-defined MPP populations may impact interpretations of how IFN-1 shapes hematopoiesis in other contexts, such as aging or inflammation.KEY POINTSLoss of type I Interferon signaling in neonatal mice depletes immature blood progenitors without compromising postnatal hematopoiesisProgenitor populations remain intact when measured by single cell transcriptomes rather than surface marker phenotypes

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“…The transformation to leukemia requires additional mutations that activate oncogenes (like FLT3 or RAS ) or inactivate tumor suppressors (like TP53 or CEBPA ) [ 175 ]. Interestingly, specifically KMT2C inactivating mutations have been shown to enhance the self-renewal capacity of hematopoietic stem cells [ 176 ].…”

Section: Consequences Of Chromatin Regulator Alterations In Urothelial Carcinomamentioning

confidence: 99%

Alterations of Chromatin Regulators in the Pathogenesis of Urinary Bladder Urothelial Carcinoma

Hoffmann

Schulz

2021

Cancers

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Urothelial carcinoma (UC) is the most frequent histological type of cancer in the urinary bladder. Genomic changes in UC activate MAPK and PI3K/AKT signal transduction pathways, which increase cell proliferation and survival, interfere with cell cycle and checkpoint control, and prevent senescence. A more recently discovered additional category of genetic changes in UC affects chromatin regulators, including histone-modifying enzymes (KMT2C, KMT2D, KDM6A, EZH2), transcription cofactors (CREBBP, EP300), and components of the chromatin remodeling complex SWI/SNF (ARID1A, SMARCA4). It is not yet well understood how these changes contribute to the development and progression of UC. Therefore, we review here the emerging knowledge on genomic and gene expression alterations of chromatin regulators and their consequences for cell differentiation, cellular plasticity, and clonal expansion during UC pathogenesis. Our analysis identifies additional relevant chromatin regulators and suggests a model for urothelial carcinogenesis as a basis for further mechanistic studies and targeted therapy development.

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Kmt2c mutations enhance HSC self-renewal capacity and convey a selective advantage after chemotherapy

Cited by 18 publications

References 67 publications

Rat and fish peripheral blood leukocytes respond distinctively to Anisakis pegreffii (Nematoda, Anisakidae) crude extract

Rat and fish peripheral blood leukocytes respond distinctively to Anisakis pegreffii (Nematoda, Anisakidae) crude extract

Basal type I interferon signaling has only modest effects on neonatal and juvenile hematopoiesis

Alterations of Chromatin Regulators in the Pathogenesis of Urinary Bladder Urothelial Carcinoma

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