Somatic mutations in children with GATA2-associated myelodysplastic syndrome who lack other features of GATA2 deficiency

Fisher, Kevin E.; Hsu, Amy P.; Williams, Christopher L.; Sayeed, Hadi; Merritt, Brian Y.; Elghetany, M. Tarek; Holland, Steven M.; Bertuch, Alison A.; Gramatges, Maria M.

doi:10.1182/bloodadvances.2016002311

Cited by 25 publications

(22 citation statements)

References 30 publications

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“…ASXL1 mutations are acquired at the time of malignancy in about 30% of cases and correlate with a chronic myelomonocytic leukemia (CMML) phenotype and monosomy 7 (75)(76)(77)(78)(79), suggesting cooperation between these genetic lesions and the germline GATA2 mutation in malignant progression. SETBP1 and STAG2 mutations are also recurrent in this setting (77,80).…”

Section: Ddx41 Srp72mentioning

confidence: 99%

Transcription factor mutations as a cause of familial myeloid neoplasms

Churpek¹,

Bresnick²

2019

Journal of Clinical Investigation

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Section: Ddx41 Srp72mentioning

confidence: 99%

Transcription factor mutations as a cause of familial myeloid neoplasms

Churpek¹,

Bresnick²

2019

Journal of Clinical Investigation

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“…Splicing donor and acceptor site mutations have also been reported, and the former are predicted to produce internally truncated GATA2. 14,15,[17][18][19] Because the transcription efficiency of the mutated allele should be comparable to that of the healthy allele, in many cases, equivalent amounts of mutated GATA2 and wildtype GATA2 proteins would be present within cells, despite the possibility that the mRNA and/or protein stability is modified (Figure 3b). We surmise that in this case, similar amounts of abnormal and wildtype GATA2 act together for the regulation of target genes (Figure 3b right panel).…”

Section: Mutations That Elicit Gata2-related Diseases: Quantitativementioning

confidence: 99%

“…In addition, a number of reports describe a variety of GATA2 gene mutations. [14][15][16][17][18][19][20][21] Distribution of the mutation types is shown in Figure 1 and Table S1. These genomic variations fall into the following categories: pathogenic, likely pathogenic, variants of uncertain significance (VUS) and likely benign.…”

Section: Introductionmentioning

confidence: 99%

“…More than 350 genomic variations of the GATA2 gene have been observed, and many of the mutations can be found in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/). In addition, a number of reports describe a variety of GATA2 gene mutations . Distribution of the mutation types is shown in Figure and Table S1.…”

Section: Introductionmentioning

confidence: 99%

“…Frequency of pathogenic or likely pathogenic variants (blue, red, green, purple, yellow, brown, and black) and the frequency of VUS or likely benign variants (white, light blue, salmon pink, bright green, and gray) in every mutation type of the GATA2 gene. The 358 genomic variations described in ClinVar and the mutations reported in the References are summarized. The percentage for each mutation type is shown in parentheses.…”

Section: Introductionmentioning

confidence: 99%

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Quantitative and qualitative impairments in GATA2 and myeloid neoplasms

Shimizu

Yamamoto

2019

IUBMB Life

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GATA2 is a key transcription factor critical for hematopoietic cell development.During the past decade, it became clear that heterozygous germline mutations in the GATA2 gene cause bone marrow failure and primary immunodeficiency syndrome, conditions that lead to a predisposition toward myeloid neoplasms, such as myelodysplastic syndrome, acute myeloid leukemia, and chronic myelomonocytic leukemia. Somatic mutations of the GATA2 gene are also involved in the pathogenesis of myeloid malignancies. Cases with GATA2 gene mutations are divided into two groups, resulting in either a quantitative deficiency or a qualitative defect in the GATA2 protein depending on the mutation position and type. In the former case, GATA2 mRNA expression from the mutant allele is markedly reduced or completely abrogated, and reduced GATA2 protein expression is involved in the pathogenesis. In the latter case, almost equal amounts of structurally abnormal and wildtype GATA2 proteins are predicted to be present and contribute to the pathogenesis. The development of mouse models of these human GATA2-related diseases has been undertaken, which naturally develop myeloid neoplasms. K E Y W O R D S disease model mice, familial MDS/AML, GATA2, quantitative or qualitative change

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Allogeneic hematopoietic cell transplantation in patients with GATA2 deficiency—a case report and comprehensive review of the literature

et al. 2018

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Recently, an immunodeficiency syndrome caused by guanine-adenine-thymine-adenine 2 (GATA2) deficiency has been described. The syndrome is characterized by (i) typical onset in early adulthood, (ii) profound peripheral blood cytopenias of monocytes, B lymphocytes, and NK cells, (iii) distinct susceptibility to disseminated non-tuberculous mycobacterial (NTM) and other opportunistic infections (particularly human papillomavirus), and (iv) a high risk of developing hematologic malignancies (myelodysplastic syndromes (MDS); acute myeloid leukemias (AML)). Considerable clinical heterogeneity exists among patients with GATA2 deficiency, but once infectious symptoms occur or MDS/AML arises, survival declines significantly. Allogeneic hematopoietic cell transplantation (HCT) currently provides the only curative treatment option for both MDS/AML and dysfunctional immunity with life-threatening opportunistic infections. Strategies regarding timing of allogeneic HCT, antimicrobial prophylaxis and treatment, intensity of the preparative regimen, and optimal donor and graft source have not been clearly defined due to the rarity of the disease. Here, we provide a comprehensive analysis of the available literature and published case reports on the use of allogeneic HCT in patients with GATA2 deficiency. In addition, a case of a young woman with GATA2 deficiency, who developed an immune reconstitution inflammatory syndrome in her mycobacterial skin lesions post allogeneic HCT is presented and illustrates distinct problems encountered in this disease context.

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Somatic mutations in children with GATA2-associated myelodysplastic syndrome who lack other features of GATA2 deficiency

Cited by 25 publications

References 30 publications

Transcription factor mutations as a cause of familial myeloid neoplasms

Transcription factor mutations as a cause of familial myeloid neoplasms

Quantitative and qualitative impairments in GATA2 and myeloid neoplasms

Allogeneic hematopoietic cell transplantation in patients with GATA2 deficiency—a case report and comprehensive review of the literature

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