Gata2 haploinsufficiency promotes proliferation and functional decline of hematopoietic stem cells with myeloid bias during aging

Abdelfattah, Ali; Hughes-Davies, Antonia; Clayfield, Liam; Menendez-Gonzalez, Juan Bautista; Almotiri, Alhomidi; Alotaibi, Badi; Tonks, Alex; Rodrigues, Neil P.

doi:10.1182/bloodadvances.2021004726

Cited by 15 publications

(14 citation statements)

References 24 publications

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“…Thus, understanding the impact of aging on GATA2-deficient HSPCs is critical. GATA2 is a master transcription factor involved in HSPC maintenance and proliferation (17). GATA2-knockout mice are born healthy, though defects in hematopoiesis can be found from birth (3,17).…”

Section: Discussionmentioning

confidence: 99%

“…GATA2 is a master transcription factor involved in HSPC maintenance and proliferation (17). GATA2-knockout mice are born healthy, though defects in hematopoiesis can be found from birth (3,17). Aging GATA2-deficient HSPCs are characterized by enhanced apoptosis and decreasing numbers (17).…”

Section: Discussionmentioning

confidence: 99%

“…GATA2-knockout mice are born healthy, though defects in hematopoiesis can be found from birth (3,17). Aging GATA2-deficient HSPCs are characterized by enhanced apoptosis and decreasing numbers (17). Therefore, GATA2 deficiency constitutes a unique primary immune deficiency (PID), as it can first manifest in adult life upon an age-related decline in the number of GATA2-deficient HSPCs (5).…”

Section: Discussionmentioning

confidence: 99%

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GATA2 Deficiency in Adult Life Is Characterized by Phenotypic Diversity and Delayed Diagnosis

et al. 2022

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The transcription factor GATA2 plays a key role in the survival and self-renewal of hematopoietic stem and progenitor cells. Autosomal dominant variants in GATA2 cause a broad spectrum of heterogeneous phenotypes. Here, we present our experience with GATA2 deficiency in a retrospective multicenter analysis of computerized medical records of adult patients (age ≥18 years) treated between 2018 and 2022 at Shaare Zedek Medical Center in Jerusalem and Sheba Tel-Hashomer Medical Center in Ramat Gan, Israel. Two male and two female patients with GATA2 deficiency were identified. Three of the patients presented with symptoms in adult life and all patients were diagnosed as adults. Age at presentation was 10.5-36 years and age at diagnosis 24-47 years. Diagnosis was delayed in all patients by 1-24.5 years. The phenotypic diversity was notable. Patients presented with myelodysplastic syndrome (n=2), pulmonary alveolar proteinosis (n=1), and recurrent viral (n=1), bacterial (n=3), and mycobacterial (n=1) infections. Bone marrow biopsy revealed cytogenetic abnormalities in one patient (monosomy 7). Patients were diagnosed by exome sequencing (n=3) and Sanger sequencing of the coding exons in GATA2 (n=1). Novel heterozygous GATA2 variants (c.177C>A, p.Y59* and c.610dup, p.R204Pfs*78) were identified in two patients. Immune workup revealed B cell lymphopenia and monocytopenia in all tested patients. One patient died from overwhelming sepsis despite all patients being treated with antibiotics and anti-mycobacterials. Our cohort highlights the phenotypic diversity, late presentation, and delayed diagnosis of GATA2 deficiency. Increased awareness of this primary immune deficiency presenting in adult life is needed and should involve a high index of suspicion.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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GATA2 Deficiency in Adult Life Is Characterized by Phenotypic Diversity and Delayed Diagnosis

et al. 2022

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“…Conditional knockout of Ebf1 converted HSC into innate lymphoid cells (ILCs) and T cells [ 176 ]. A Gata2 mutation in one of the DNA strands results in haploinsufficiency, which also causes a myeloid bias in HSPCs [ 177 ].…”

Section: Hscs Adulthood and Agingmentioning

confidence: 99%

Hematopoietic Stem Cells and the Immune System in Development and Aging

Shevyrev

Tereshchenko

Berezina

et al. 2023

IJMS

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Hematopoietic stem cells (HSCs) support haematopoiesis throughout life and give rise to the whole variety of cells of the immune system. Developing in the early embryo, passing through the precursor stage, and maturing into the first HSCs, they undergo a fairly large number of divisions while maintaining a high regenerative potential due to high repair activity. This potential is greatly reduced in adult HSCs. They go into a state of dormancy and anaerobic metabolism to maintain their stemness throughout life. However, with age, changes occur in the pool of HSCs that negatively affect haematopoiesis and the effectiveness of immunity. Niche aging and accumulation of mutations with age reduces the ability of HSCs to self-renew and changes their differentiation potential. This is accompanied by a decrease in clonal diversity and a disturbance of lymphopoiesis (decrease in the formation of naive T- and B-cells) and the predominance of myeloid haematopoiesis. Aging also affects mature cells, regardless of HSC, therefore, phagocytic activity and the intensity of the oxidative burst decrease, and the efficiency of processing and presentation of antigens by myeloid cells is impaired. Aging cells of innate and adaptive immunity produce factors that form a chronic inflammatory background. All these processes have a serious negative impact on the protective properties of the immune system, increasing inflammation, the risk of developing autoimmune, oncological, and cardiovascular diseases with age. Understanding the mechanisms of reducing the regenerative potential in a comparative analysis of embryonic and aging HSCs, the features of inflammatory aging will allow us to get closer to deciphering the programs for the development, aging, regeneration and rejuvenation of HSCs and the immune system.

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“… 23 Germline GATA2 mutations 24 , 25 , 26 , 27 , 28 , 29 , 30 cause bone marrow failure and leukemia predisposition, and the mechanisms are being dissected in adults. 31 , 32 , 33 , 34 , 35 , 36 GATA2 expression in HSPCs is conferred by two enhancers, 77 and 9.5 kb upstream and downstream, respectively, of the mouse Gata2 start site. 25 , 31 , 32 , 37 , 38 , 39 Whereas the +9.5 enhancer triggers the emergence of HSCs in the aorta, gonad, and mesonephros region, 40 the −77 enhancer is dispensable for HSC genesis.…”

Section: Introductionmentioning

confidence: 99%

Restricting genomic actions of innate immune mediators on fetal hematopoietic progenitor cells

Tran¹,

Liu²,

Katsumura³

et al. 2023

iScience

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Gata2 haploinsufficiency promotes proliferation and functional decline of hematopoietic stem cells with myeloid bias during aging

Cited by 15 publications

References 24 publications

GATA2 Deficiency in Adult Life Is Characterized by Phenotypic Diversity and Delayed Diagnosis

GATA2 Deficiency in Adult Life Is Characterized by Phenotypic Diversity and Delayed Diagnosis

Hematopoietic Stem Cells and the Immune System in Development and Aging

Restricting genomic actions of innate immune mediators on fetal hematopoietic progenitor cells

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