GATA2 finds its macrophage niche

Migliaccio, Anna Rita; Bieker, James J.

doi:10.1182/blood-2011-06-362772

Cited by 7 publications

(3 citation statements)

References 15 publications

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“…Moreover, the increase in immature colony proportion with WT-GATA2 and not with p.Arg396Gln further suggests that although WT-GATA2 retains the immature phenotype, p.Arg396Gln fails to do so. It has been suggested that hyperstimulation of the stem cell pool that produces hematopoietic progenitor cells with reduced expansion potential may lead to stem cell exhaustion in MonoMAC and dendritic cell, monocyte, and B and NK lymphoid deficiency syndromes (29). Our results would indicate that, in the context of these syndromes, p.Arg396Gln would force HSPCs to divide and differentiate prematurely, which would gradually drain the stem cell pool.…”

Section: Discussionmentioning

confidence: 64%

GATA2 Germline Mutations Impair GATA2 Transcription, Causing Haploinsufficiency: Functional Analysis of the p.Arg396Gln Mutation

Cortés-Lavaud

Landecho

Maicas

et al. 2015

The Journal of Immunology

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Germline GATA2 mutations have been identified as the cause of familial syndromes with immunodeficiency and predisposition to myeloid malignancies. GATA2 mutations appear to cause loss of function of the mutated allele leading to haploinsufficiency; however, this postulate has not been experimentally validated as the basis of these syndromes. We hypothesized that mutations that are translated into abnormal proteins could affect the transcription of GATA2, triggering GATA2 deficiency. Chromatin immunoprecipitation and luciferase assays showed that the human GATA2 protein activates its own transcription through a specific region located at −2.4 kb, whereas the p.Thr354Met, p.Thr355del, and p.Arg396Gln germline mutations impair GATA2 promoter activation. Accordingly, GATA2 expression was decreased to ∼58% in a patient with p.Arg396Gln, compared with controls. p.Arg396Gln is the second most common mutation in these syndromes, and no previous functional analyses have been performed. We therefore analyzed p.Arg396Gln. Our data show that p.Arg396Gln is a loss-of-function mutation affecting DNA-binding ability and, as a consequence, it fails to maintain the immature characteristics of hematopoietic stem and progenitor cells, which could result in defects in this cell compartment. In conclusion, we show that human GATA2 binds to its own promoter, activating its transcription, and that the aforementioned mutations impair the transcription of GATA2. Our results indicate that they can affect other GATA2 target genes, which could partially explain the variability of symptoms in these diseases. Moreover, we show that p.Arg396Gln is a loss-of-function mutation, which is unable to retain the progenitor phenotype in cells where it is expressed.

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Section: Discussionmentioning

confidence: 64%

GATA2 Germline Mutations Impair GATA2 Transcription, Causing Haploinsufficiency: Functional Analysis of the p.Arg396Gln Mutation

Cortés-Lavaud

Landecho

Maicas

et al. 2015

The Journal of Immunology

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“…7E). Some of these genes are transcription factors (Gata2, Egr1, Egr3, Inhba) and have been associated with monocyte/macrophage growth and differentiation (29)(30)(31). The IL-7 receptor (IL-7R) network was also affected.…”

Section: Figmentioning

confidence: 99%

Conservation of Intracellular Pathogenic Strategy among Distantly Related Cryptococcal Species

Freij

Rodriguez

et al. 2018

Infect Immun

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The genus includes several species pathogenic for humans. Until recently, the two major pathogenic species were recognized to be and We compared the interaction of murine macrophages with three species complex strains (WM179, R265, and WM161, representing molecular types VGI, VGIIa, and VGIII, respectively) and one species complex strain (H99, molecular type VNI) to ascertain similarities and differences in the yeast intracellular pathogenic strategy. The parameters analyzed included nonlytic exocytosis frequency, phagolysosomal pH, intracellular capsular growth, phagolysosomal membrane permeabilization, and macrophage transcriptional response, assessed using time-lapse microscopy, fluorescence microscopy, flow cytometry, and gene expression microarray analysis. The most striking result was that the intracellular pathogenic strategies of and species complex strains were qualitatively similar, despite the species having separated an estimated 100 million years ago. Macrophages exhibited a leaky phagolysosomal membrane phenotype and nonlytic exocytosis when infected with either or Conservation of the intracellular strategy among species that separated long ago suggests that it is ancient and possibly maintained by similar selection pressures through eons.

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“…It was suggested that the increased incidence of MDS in patients with GATA-2 mutation-induced MonoMAC syndrome may result from defective regulation of HSC proliferation: in the face of systemic immune dysfunction and recurrent infection, the stem cell compartment is stimulated to proliferate, and since committed progenitors are also dysfunctional due to GATA-2 haploinsufficiency, this leads to chronic stress on the HSC compartment, HSC exhaustion and MDS (163). GATA-2 haploinsufficient mice have a decreased stem cell pool, with a higher percentage of quiescent LSK cells and increased apoptosis (32).…”

Section: Human Pathophysiologies Caused By Gata-2 Dysregulationmentioning

confidence: 99%

Master regulatory GATA transcription factors: mechanistic principles and emerging links to hematologic malignancies

Bresnick

Katsumura

Lee

et al. 2012

Nucleic Acids Research

162

173

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Numerous examples exist of how disrupting the actions of physiological regulators of blood cell development yields hematologic malignancies. The master regulator of hematopoietic stem/progenitor cells GATA-2 was cloned almost 20 years ago, and elegant genetic analyses demonstrated its essential function to promote hematopoiesis. While certain GATA-2 target genes are implicated in leukemogenesis, only recently have definitive insights emerged linking GATA-2 to human hematologic pathophysiologies. These pathophysiologies include myelodysplastic syndrome, acute myeloid leukemia and an immunodeficiency syndrome with complex phenotypes including leukemia. As GATA-2 has a pivotal role in the etiology of human cancer, it is instructive to consider mechanisms underlying normal GATA factor function/regulation and how dissecting such mechanisms may reveal unique opportunities for thwarting GATA-2-dependent processes in a therapeutic context. This article highlights GATA factor mechanistic principles, with a heavy emphasis on GATA-1 and GATA-2 functions in the hematopoietic system, and new links between GATA-2 dysregulation and human pathophysiologies.

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GATA2 finds its macrophage niche

Cited by 7 publications

References 15 publications

GATA2 Germline Mutations Impair GATA2 Transcription, Causing Haploinsufficiency: Functional Analysis of the p.Arg396Gln Mutation

GATA2 Germline Mutations Impair GATA2 Transcription, Causing Haploinsufficiency: Functional Analysis of the p.Arg396Gln Mutation

Conservation of Intracellular Pathogenic Strategy among Distantly Related Cryptococcal Species

Master regulatory GATA transcription factors: mechanistic principles and emerging links to hematologic malignancies

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