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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6119136PMC
http://dx.doi.org/10.3324/haematol.2017.180844DOI Listing

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Article Synopsis
  • - Gfi1 is a crucial transcriptional repressor involved in blood cell development, mainly working through its SNAG domain to recruit the histone demethylase LSD1, affecting gene regulation.
  • - The study reveals Gfi1's ability to enhance the expression of the Hemgn gene via a specific promoter region, with interactions from transcription factors like Ikaros (which activates Hemgn) and PU.1 (which represses it).
  • - Gfi1's upregulation of Hemgn not only occurs through repression of PU.1 but also contributes to Gfi1's protective role against cell death caused by stress, independent of the p53 protein.
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Neutrophil metalloproteinase driven spleen damage hampers infection control of trypanosomiasis.

Nat Commun

September 2023

Laboratory for Biomedical Research, Department of Environmental Technology, Food Technology and Molecular Biotechnology KR01, Ghent University Global Campus, Incheon, South Korea.

Recent blood transcriptomic analysis of rhodesiense sleeping sickness patients has revealed that neutrophil signature genes and activation markers constitute the top indicators of trypanosomiasis-associated inflammation. Here, we show that Trypanosoma brucei infection results in expansion and differentiation of four splenic neutrophil subpopulations, including Mki67Birc5Gfi1Cebpe proliferation-competent precursors, two intermediate immature subpopulations and CebpbSpi1Irf7Mcl1Csf3r inflammation reprogrammed mature neutrophils. Transcriptomic scRNA-seq profiling identified the largest immature subpopulation by Mmp8/9 positive tertiary granule markers.

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Lsd1/Kdm1a functions both as a histone demethylase enzyme and as a scaffold for assembling chromatin modifier and transcription factor complexes to regulate gene expression. The relative contributions of Lsd1's demethylase and scaffolding functions during embryogenesis are not known. Here, we analyze two independent zebrafish mutant lines and show Lsd1 is required to repress primitive hematopoietic stem cell gene expression.

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HMG20B stabilizes association of LSD1 with GFI1 on chromatin to confer transcription repression and leukemia cell differentiation block.

Oncogene

October 2022

Leukaemia Biology Laboratory, Cancer Research UK Manchester Institute, The University of Manchester, Manchester Cancer Research Centre Building, 555 Wilmslow Road, Manchester, M20 4GJ, UK.

Pharmacologic inhibition of LSD1 induces molecular and morphologic differentiation of blast cells in acute myeloid leukemia (AML) patients harboring MLL gene translocations. In addition to its demethylase activity, LSD1 has a critical scaffolding function at genomic sites occupied by the SNAG domain transcription repressor GFI1. Importantly, inhibitors block both enzymatic and scaffolding activities, in the latter case by disrupting the protein:protein interaction of GFI1 with LSD1.

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Unlabelled: Growth factor independence-1 (GFI1) is a transcriptional repressor and master regulator of normal and malignant hematopoiesis. Repression by GFI1 is attributable to recruitment of LSD1-containing protein complexes via its SNAG domain. However, the full complement of GFI1 partners in transcriptional control is not known.

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