<i>Gata2</i>-regulated <i>Gfi1b</i> expression controls endothelial programming during endothelial-to-hematopoietic transition

Koyunlar, Cansu; Gioacchino, Emanuele; Vadgama, Disha; Looper, Hans W.J. de; Peulen-Zink, Joke; Borg, Mariëtte ter; Hoogenboezem, Remco M.; Havermans, Marije; Sanders, Mathijs A.; Bindels, Eric; Dzierzak, Elaine; Touw, Ivo P.; Pater, Emma de

doi:10.1182/bloodadvances.2022008019

Cited by 4 publications

(3 citation statements)

References 46 publications

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“…Furthermore, the mutated LT-HSCs expressed genes that are typically expressed in microenvironment cells rather than in hematopoietic cells. This observation is consistent with the findings from the De Pater's group 63 , which demonstrated impairment in suppressing endothelial identity in Gata2 +/-HSPCs during embryonic maturation due to a reduced Gfi1b activity. This reduction was also observed in Gata2 R396Q/+ LT-HSCs.…”

Section: Discussionsupporting

confidence: 93%

Loss of HSC stemness identity is associated with exhaustion and hyporesponsiveness in GATA2 deficiency syndrome

Largeaud,

Fregona,

Jamrog

et al. 2023

Preprint

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GermlineGATA2mutations lead to a syndrome involving both immunodeficiency and myeloid malignancies. Since GATA2 is a key player in hematopoietic initiation and development, we specify the impact of these germline mutations on hematopoietic homeostasis by generated a knock-in mouse model expressing the recurrentGata2R396Q missense mutation. These mice exhibit a hematopoietic stem and progenitor cell (HSPC) compartment profoundly impacted with increased HSC number, decreased self-renewal potential and inability to respond to acute inflammatory stimuli. Moreover, mutated HSPCs are predisposed to be hyporesponsive, as evidenced by lower interferon signaling and enrichment of inflammatory stress signatures. Furthermore, a Gata2 allelic specific expression results in a molecular and functional heterogeneity of the mutated Long Term-HSC population. Altogether, we highlight that Gata2 plays a crucial role in the ability of HSCs to perceive and respond to their environment, and that germline mutation contributes to the decline in HSC functionality.

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Section: Discussionsupporting

confidence: 93%

Loss of HSC stemness identity is associated with exhaustion and hyporesponsiveness in GATA2 deficiency syndrome

Largeaud,

Fregona,

Jamrog

et al. 2023

Preprint

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“…Gata2 depletion also reduces multi-lineage potential in mice, as well as HSPC cell numbers ( 171 ). Haploinsufficiency does not completely diminish hematopoietic programming but reduces the capacity of HSPCs to complete HSC maturation during the endothelial to hematopoietic transition, where Gata2(+/-) is able to initiate the process, but unable to fully execute it ( 172 ). Knockout mice exhibit near entire loss of HSCs, primitive progenitor cells and committed myeloid and erythroid progenitors ( 170 ), whilst GATA2(+/-) mice show markedly reduced HSC numbers suggesting dose-dependence.…”

Section: Biological Mechanisms Of Bmf And/or Hm Predisposition Tfsmentioning

confidence: 99%

Transcription factor genetics and biology in predisposition to bone marrow failure and hematological malignancy

Zerella,

Homan,

Arts

et al. 2023

Front. Oncol.

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Transcription factors (TFs) play a critical role as key mediators of a multitude of developmental pathways, with highly regulated and tightly organized networks crucial for determining both the timing and pattern of tissue development. TFs can act as master regulators of both primitive and definitive hematopoiesis, tightly controlling the behavior of hematopoietic stem and progenitor cells (HSPCs). These networks control the functional regulation of HSPCs including self-renewal, proliferation, and differentiation dynamics, which are essential to normal hematopoiesis. Defining the key players and dynamics of these hematopoietic transcriptional networks is essential to understanding both normal hematopoiesis and how genetic aberrations in TFs and their networks can predispose to hematopoietic disease including bone marrow failure (BMF) and hematological malignancy (HM). Despite their multifaceted and complex involvement in hematological development, advances in genetic screening along with elegant multi-omics and model system studies are shedding light on how hematopoietic TFs interact and network to achieve normal cell fates and their role in disease etiology. This review focuses on TFs which predispose to BMF and HM, identifies potential novel candidate predisposing TF genes, and examines putative biological mechanisms leading to these phenotypes. A better understanding of the genetics and molecular biology of hematopoietic TFs, as well as identifying novel genes and genetic variants predisposing to BMF and HM, will accelerate the development of preventative strategies, improve clinical management and counseling, and help define targeted treatments for these diseases.

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“…Deletion of the conserved E-box-GATA composite element from the +9.5 of mice resulted in failure to generate hematopoietic stem cells in the aorta-gonad mesonephros (AGM) and embryonic lethality by embryonic day (E) 14.5 [9,34]. GATA2-regulated endothelial to hematopoietic transition [34,35] involves the regulation of many genes in hemogenic endothelial cells and hematopoietic stem and progenitor cell (HSPC) progeny, include the transcription factor GFI1b [34], which promotes the endothelial to hematopoietic transition downstream of GATA2 [36 ▪ ]. Although loss of a +9.5 ETS motif, or a single-nucleotide alteration in this motif that can occur in GATA2 deficiency syndrome patients can be tolerated during development and homeostasis, these alterations create a vulnerability in stress hematopoiesis [10,37,38].…”

Section: Text Of Reviewmentioning

confidence: 99%

Interferon regulatory factor-8-dependent innate immune alarm senses GATA2 deficiency to alter hematopoietic differentiation and function

Johnson

Jung

Tran

et al. 2023

Current Opinion in Hematology

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Purpose of reviewRecent discoveries have provided evidence for mechanistic links between the master regulator of hematopoiesis GATA2 and the key component of interferon and innate immunity signaling pathways, interferon-regulatory factor-8 (IRF8). These links have important implications for the control of myeloid differentiation in physiological and pathological states.Recent findingsGATA2 deficiency resulting from loss of the Gata2 −77 enhancer in progenitors triggers an alarm that instigates the transcriptional induction of innate immune signaling and distorts a myeloid differentiation program. This pathological alteration renders progenitors hyperresponsive to interferon γ, toll-like receptor and interleukin-6 signaling and impaired in granulocyte-macrophage colony-stimulating factor signaling. IRF8 upregulation in −77−/− progenitors promotes monocyte and dendritic cell differentiation while suppressing granulocytic differentiation. As PU.1 promotes transcription of Irf8 and other myeloid and B-lineage genes, GATA2-mediated repression of these genes opposes the PU.1-dependent activating mechanism.SummaryAs GATA2 deficiency syndrome is an immunodeficiency disorder often involving myelodysplastic syndromes and acute myeloid leukemia, elucidating how GATA2 commissions and decommissions genome activity and developmental regulatory programs will unveil mechanisms that go awry when GATA2 levels and/or activities are disrupted.

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Gata2-regulated Gfi1b expression controls endothelial programming during endothelial-to-hematopoietic transition

Cited by 4 publications

References 46 publications

Loss of HSC stemness identity is associated with exhaustion and hyporesponsiveness in GATA2 deficiency syndrome

Loss of HSC stemness identity is associated with exhaustion and hyporesponsiveness in GATA2 deficiency syndrome

Transcription factor genetics and biology in predisposition to bone marrow failure and hematological malignancy

Interferon regulatory factor-8-dependent innate immune alarm senses GATA2 deficiency to alter hematopoietic differentiation and function

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