GATA2 haploinsufficiency caused by mutations in a conserved intronic element leads to MonoMAC syndrome

Hsu, Amy P.; Johnson, Kirby D.; Falcone, Emilia Liana; Sanalkumar, Rajendran; Sanchez, Lauren A.; Hickstein, Dennis D.; Cuéllar-Rodríguez, Jennifer; Lemieux, Jacob E.; Zerbe, Christa S.; Bresnick, Emery H.; Holland, Steven M.

doi:10.1182/blood-2012-08-452763

Cited by 214 publications

(207 citation statements)

References 37 publications

(56 reference statements)

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“…We observed a disturbed maturation profile with an accumulation of CD16 10 Non-RCC and AA patients presented with fewer granulocytes than the remaining cohorts, including controls (Table 3). In PB, neutropenia was frequently present in GATA-2-deficient patients ( Figure 3B), and at least some of the absolute neutrophil count (ANC) values were below 1x10 9 /L in all but one patient (UPN7). NK lymphopenia was present in half of the GATA-2-deficient cases ( Figure 3B).…”

Section: Myeloid Populations and Nk Cells In Gata-2 Deficiencymentioning

confidence: 99%

“…Fanconi anemia, dyskeratosis congenita or ShwachmanDiamond syndrome). 5 A mutation in the GATA2 gene, which encodes the transcription factor GATA-2, was recently found by whole genome sequencing 6,7 or by candidate approaches 8,9 as a common cause of several overlapping syndromes: familial MDS/acute myeloid leukemia (AML), dendritic cell, monocyte, B-and NK-lymphoid (DCML) deficiency, mycobacterial infections and monocytopenia (MonoMAC), and hereditary lymphedema (Emberger syndrome). 6,7 Several abnormalities, identifiable by flow cytometry (FC) in peripheral blood (PB), are known to be present in patients with GATA2 mutations: a decreased number of B cells, NK cells, monocytes and dendritic cells; 10,11 plasma cells with an aberrant immunophenotype in bone marrow (BM); clonal T-large granular lymphocyte (LGL) proliferation; and aberrant maturation patterns of granulocytic lineage.…”

Section: Loss Of B Cells and Their Precursors Is The Most Constant Fementioning

confidence: 99%

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Loss of B cells and their precursors is the most constant feature of GATA-2 deficiency in childhood myelodysplastic syndrome

et al. 2016

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Section: Myeloid Populations and Nk Cells In Gata-2 Deficiencymentioning

confidence: 99%

Section: Loss Of B Cells and Their Precursors Is The Most Constant Fementioning

confidence: 99%

Loss of B cells and their precursors is the most constant feature of GATA-2 deficiency in childhood myelodysplastic syndrome

et al. 2016

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“…Following NeoR excision, the targeted allele has a 126-bp Xba I-to-Not I fragment containing a single LoxP site substituted for the GATA motifs and intervening sequence. or near the +9.5 site (5,45). Thus, mutations of the +9.5 element, an essential mediator of definitive hematopoiesis in the mouse, underlie human hematopoietic pathology.…”

Section: Significancementioning

confidence: 99%

Mechanism governing a stem cell-generating cis -regulatory element

Sanalkumar

Johnson

Gào

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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The unremitting demand to replenish differentiated cells in tissues requires efficient mechanisms to generate and regulate stem and progenitor cells. Although master regulatory transcription factors, including GATA binding protein-2 (GATA-2), have crucial roles in these mechanisms, how such factors are controlled in developmentally dynamic systems is poorly understood. Previously, we described five dispersed Gata2 locus sequences, termed the −77, −3.9, −2.8, −1.8, and +9.5 GATA switch sites, which contain evolutionarily conserved GATA motifs occupied by GATA-2 and GATA-1 in hematopoietic precursors and erythroid cells, respectively. Despite common attributes of transcriptional enhancers, targeted deletions of the −2.8, −1.8, and +9.5 sites revealed distinct and unpredictable contributions to Gata2 expression and hematopoiesis. Herein, we describe the targeted deletion of the −3.9 site and mechanistically compare the −3.9 site with other GATA switch sites. The −3.9 −/− mice were viable and exhibited normal Gata2 expression and steady-state hematopoiesis in the embryo and adult. We established a Gata2 repression/reactivation assay, which revealed unique +9.5 site activity to mediate GATA factor-dependent chromatin structural transitions. Loss-of-function analyses provided evidence for a mechanism in which a mediator of long-range transcriptional control [LIM domain binding 1 (LDB1)] and a chromatin remodeler [Brahma related gene 1 (BRG1)] synergize through the +9.5 site, conferring expression of GATA-2, which is known to promote the genesis and survival of hematopoietic stem cells.cis element | HSCs W hereas proximal promoter sequences assemble the basal transcriptional machinery and RNA polymerase, distant cis-regulatory elements often confer tissue-specific or contextdependent transcriptional regulation. Enhancer elements reside many kilobases upstream or downstream of a promoter or within introns, and extensive efforts have focused on elucidating "action-at-a-distance" mechanisms (1). Long-range transcriptional control involves physical interactions between proteins bound at distal regions and promoter sequences and higher order structural transitions, including subnuclear relocalization of target loci (2-4). Given the high frequency of long-range mechanisms at mammalian loci and the mutations that disrupt the function of such elements in pathological conditions, elucidating the underlying mechanisms in development,

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“…The germline GATA2 mutations are often truncating mutations, resulting in the loss of second zinc finger domain (ZF2), or missense mutations in ZF2 or the noncoding regulatory region, resulting in haploinsufficiency of GATA2. [49][50][51][52] Germline GATA2 mutation is associated with a broad spectrum of phenotypes, encompassing hematologic disease such as AML and MDS; infection characterized by viral, mycobacterial, and fungal infection; immunodeficiency with monocytopenia; B-and NK-cell lymphocytopenia; skin conditions with warts and panniculitis; pulmonary disorder; and vascular/lymphatic dysfunction. 52,53 These features can be variably present and provide clinical clues, but may also be absent.…”

Section: Myeloid Neoplasms With Germline Gata2 Mutationmentioning

confidence: 99%

Myeloid Neoplasm With Germline Predisposition: A 2016 Update for Pathologists

Gao

Gong

Chen

2018

Archives of Pathology &Amp; Laboratory Medicine

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Context.— Myeloid neoplasms with familial occurrence have been rarely reported in the past. With the advance of molecular technology and better understanding of the molecular pathogenesis of myeloid neoplasms, investigating the genetic causes of familial acute myeloid leukemia or myelodysplastic syndrome has become feasible in the clinical setting. Recent studies have identified a rapidly expanding list of germline mutations associated with increased risks of developing myeloid neoplasm in the affected families. It is important to recognize these entities, as such a diagnosis may dictate a unique approach in clinical management and surveillance for the patients and carriers. Objective.— To raise the awareness of myeloid neoplasms arising in the setting of familial inheritance among practicing pathologists. Data Sources.— Based on recent literature and the 2016 revision of the World Health Organization classification of hematopoietic neoplasms, we provide an up-to-date review of myeloid neoplasm with germline predisposition. Conclusions.— This short review focuses on the clinical, pathologic, and molecular characterization of myeloid neoplasm with germline predisposition. We emphasize the important features that will help practicing pathologists to recognize these newly described entities.

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GATA2 haploinsufficiency caused by mutations in a conserved intronic element leads to MonoMAC syndrome

Abstract: Key Points Mutations in a conserved intronic enhancer element lead to GATA2 haploinsufficiency. Mutations in GATA2, regardless of mutation type, lead to decreased GATA2 transcript levels and a common global transcriptional profile.

Cited by 214 publications

References 37 publications

Loss of B cells and their precursors is the most constant feature of GATA-2 deficiency in childhood myelodysplastic syndrome

Loss of B cells and their precursors is the most constant feature of GATA-2 deficiency in childhood myelodysplastic syndrome

Mechanism governing a stem cell-generating cis -regulatory element

Myeloid Neoplasm With Germline Predisposition: A 2016 Update for Pathologists

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