<i>Gata2</i> +9.5 enhancer regulates adult hematopoietic stem cell self-renewal and T-cell development

You, Xiaona; Zhou, Yun; Chang, Yuh‐Fang; Kong, Guangyao; Ranheim, Erik A.; Johnson, Kirby D.; Soukup, Alexandra A.; Bresnick, Emery H.; Zhang, Jing

doi:10.1182/bloodadvances.2021004311

Cited by 6 publications

(6 citation statements)

References 12 publications

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“…Notably, when compare with the Gata2 +/or Gata2 +9.5 +/mouse models 57 both exhibiting lower expression of Gata2, the Gata2 R396Q/+ and Gata2 R398W/+ murine models with missense mutations demonstrate no reduction in overall Gata2 expression in the LSK compartment 17 . This observation suggests the existence of mechanistic variations depending on the specific type of mutation.…”

Section: Discussionmentioning

confidence: 90%

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: Discussionmentioning

confidence: 90%

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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“…We asked if CH variation rendered these populations apoptotic. 32 , 39 Although Annexin V + CH HSCs increased 1.8-fold relative to WT ( P = .002) 16 hours after G-CSF administration, there was no increase with vehicle alone. CH MPP apoptosis increased (1.6- to 3.1-fold vs WT MPP) ( P = .02, .04, and .02 with vehicle, 4 hours, and 16 hours G-CSF, respectively) regardless of treatment ( Figure 2 D; supplemental Figure 3 B).…”

Section: Resultsmentioning

confidence: 96%

Gata2 noncoding genetic variation as a determinant of hematopoietic stem/progenitor cell mobilization efficiency

Soukup,

Bresnick

2023

Blood Advances

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Germline genetic variants alter the coding and enhancer sequences of GATA2, which encodes a master regulator of hematopoiesis. The conserved murine Gata2 enhancer (+9.5) promotes hematopoietic stem cell (HSC) genesis during embryogenesis. Heterozygosity for a single-nucleotide Ets motif variant in the human enhancer creates a bone marrow failure and acute myeloid leukemia predisposition termed GATA2 deficiency syndrome. The homozygous murine variant attenuates chemotherapy- and transplantation-induced hematopoietic regeneration, hematopoietic stem and progenitor cell (HSPC) response to inflammation, and HSPC mobilization with the therapeutic mobilizer G-CSF. As a Gata2 +9.5 variant attenuated G-CSF-induced HSPC expansion and mobilization, and HSC transplantation therapies require efficacious mobilization, we tested whether variation impacts mechanistically distinct mobilizers or only those operating through select pathways. In addition to affecting G-CSF activity, Gata2 variation compromised IL-8/CXCR2- and VLA-4/VCAM1-induced mobilization. While the variation did not disrupt HSPC mobilization mediated by plerixafor, which functions through CXCR4/CXCL12, homozygous and heterozygous variation attenuated mobilization efficacy of the clinically used plerixafor/G-CSF combination. The influence of non-coding variation on HSPC mobilization efficacy and function is important clinically since comprehensive non-coding variation is not commonly analyzed in patients. Furthermore, our mobilization-defective system offers unique utility for elucidating fundamental HSPC mechanisms.

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“…Unlike Nras G12D HSPCs with balanced expansion in myeloid and lymphoid compartments, NP mut HSPCs showed imbalanced myelopoiesis and lymphopoiesis ( Figure 2A ), to which both cell-autonomous and cell-nonautonomous mechanisms may contribute. We previously reported that GATA2 downregulation in HSPCs reduces lymphoid progenitors and the reconstitution of T cells in comparison with WT HSPCs ( 67 ). Consistently in this study, we found that decreased GATA2 expression in NP mut HSPCs was associated with lymphopenia ( Figure 5 ), suggesting that mutant p53 and oncogenic NRAS cooperated to downregulate GATA2 and regulate hematopoiesis in a cell-autonomous manner.…”

Section: Discussionmentioning

confidence: 99%

A gain-of-function p53 mutant synergizes with oncogenic NRAS to promote acute myeloid leukemia in mice

Rajagopalan,

Feng,

Gayatri

et al. 2023

Journal of Clinical Investigation

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We previously demonstrated that a subset of acute myeloid leukemia (AML) patients with concurrent RAS pathway and TP53 mutations have an extremely poor prognosis and that most of these TP53 mutations are missense mutations. Here, we report that, in contrast to the mixed AML and T cell malignancy that developed in Nras G12D/+ p53 –/– (NP –/– ) mice, Nras G12D/+ p53 R172H/+ (NP mut ) mice rapidly developed inflammation-associated AML. Under the inflammatory conditions, NP mut hematopoietic stem and progenitor cells (HSPCs) displayed imbalanced myelopoiesis and lymphopoiesis and mostly normal cell proliferation despite MEK/ERK hyperactivation. RNA-Seq analysis revealed that oncogenic NRAS signaling and mutant p53 synergized to establish an NP mut -AML transcriptome distinct from that of NP –/– cells. The NP mut -AML transcriptome showed GATA2 downregulation and elevated the expression of inflammatory genes, including those linked to NF-κB signaling. NF-κB was also upregulated in human NRAS TP53 AML. Exogenous expression of GATA2 in human NP mut KY821 AML cells downregulated inflammatory gene expression. Mouse and human NP mut AML cells were sensitive to MEK and NF-κB inhibition in vitro. The proteasome inhibitor bortezomib stabilized the NF-κB–inhibitory protein IκBα, reduced inflammatory gene expression, and potentiated the survival benefit of a MEK inhibitor in NP mut mice. Our study demonstrates that a p53 structural mutant synergized with oncogenic NRAS to promote AML through mechanisms distinct from p53 loss.

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Gata2 +9.5 enhancer regulates adult hematopoietic stem cell self-renewal and T-cell development

Cited by 6 publications

References 12 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

Gata2 noncoding genetic variation as a determinant of hematopoietic stem/progenitor cell mobilization efficiency

A gain-of-function p53 mutant synergizes with oncogenic NRAS to promote acute myeloid leukemia in mice

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