Heterogeneity of GATA2-related myeloid neoplasms

Hirabayashi, Shinsuke; Wlodarski, Marcin W.; Kozyra, Emilia J; Niemeyer, Charlotte M.

doi:10.1007/s12185-017-2285-2

Cited by 44 publications

(43 citation statements)

References 44 publications

(57 reference statements)

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“…GATA2 and SAMD9/SAMD9L syndromes are the most frequent predisposing conditions in children and adolescents with primary MDS and are associated with the development of monosomy 7: collectively they account for at least 50% of pediatric MDS with monosomy 7 [ 30 , [37] , [38] , [39] ]. The following text will discuss in detail the clinical and genetic spectrum of GATA2 and SAMD9/SAMD9L syndromes.…”

Section: Introduction: Germline Predisposition In Myeloid Neoplasmsmentioning

confidence: 99%

Germline predisposition in myeloid neoplasms: Unique genetic and clinical features of GATA2 deficiency and SAMD9/SAMD9L syndromes

Sahoo

Kozyra

Wlodarski

2020

Best Practice & Research Clinical Haematology

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Increasing awareness about germline predisposition and the widespread application of unbiased whole exome sequencing contributed to the discovery of new clinical entities with high risk for the development of haematopoietic malignancies. The revised 2016 WHO classification introduced a novel category of “myeloid neoplasms with germline predisposition” with GATA2 , CEBPA , DDX41 , RUNX1 , ANKRD26 , and ETV6 genes expanding the spectrum of hereditary myeloid neoplasms (MN). Since then, more germline causes of MN were identified, including SAMD9 , SAMD9L , and ERCC6L2 . This review describes the genetic and clinical spectrum of predisposition to MN. The main focus lies in delineation of phenotypes, genetics and management of GATA2 deficiency and the novel SAMD9/SAMD9L-related disorders. Combined, GATA2 and SAMD9/SAMD9L (SAMD9/9L) syndromes are recognized as most frequent causes of primary pediatric myelodysplastic syndromes, particularly in setting of monosomy 7. To date, ∼550 cases with germline GATA2 mutations, and ∼130 patients with SAMD9/9L mutations had been reported in literature. GATA2 deficiency is a highly penetrant disorder with a progressive course that often rapidly necessitates bone marrow transplantation. In contrast, SAMD9/SAMD9L disorders show incomplete penetrance with various clinical outcomes ranging from spontaneous haematological remission observed in young children to malignant progression.

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Section: Introduction: Germline Predisposition In Myeloid Neoplasmsmentioning

confidence: 99%

Germline predisposition in myeloid neoplasms: Unique genetic and clinical features of GATA2 deficiency and SAMD9/SAMD9L syndromes

Sahoo

Kozyra

Wlodarski

2020

Best Practice & Research Clinical Haematology

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“…34,35 According to estimates, 75% of patients with GATA2 haploinsufficiency progress to MDS/AML by ;18 years of age. 13,34,36,37 The phenotype severity and onset before and during reproductive age likely underlie significant selection against GATA2 LoF, a phenomenon we also observed in several other myeloid malignancy predisposition genes (eg, RUNX1, MECOM, ETV6). In contrast, germline heterozygous LoF variants in DDX41 have been implicated in the development of MDS/AML in older adults with a mean age of 62 years.…”

Section: Spectrum Of Mutational Constraint On Ibmf Genesmentioning

confidence: 53%

Human mutational constraint as a tool to understand biology of rare and emerging bone marrow failure syndromes

et al. 2020

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Inherited bone marrow failure (IBMF) syndromes are rare blood disorders characterized by hematopoietic cell dysfunction and predisposition to hematologic malignancies. Despite advances in the understanding of molecular pathogenesis of these heterogeneous diseases, genetic variant interpretation, genotype–phenotype correlation, and outcome prognostication remain difficult. As new IBMF and other myelodysplastic syndrome (MDS) predisposition genes continue to be discovered (frequently in small kindred studies), there is an increasing need for a systematic framework to evaluate penetrance and prevalence of mutations in genes associated with IBMF phenotypes. To address this need, we analyzed population-based genomic data from >125 000 individuals in the Genome Aggregation Database for loss-of-function (LoF) variants in 100 genes associated with IBMF. LoF variants in genes associated with IBMF/MDS were present in 0.426% of individuals. Heterozygous LoF variants in genes in which haploinsufficiency is associated with IBMF/MDS were identified in 0.422% of the population; homozygous LoF variants associated with autosomal recessive IBMF/MDS diseases were identified in only .004% of the cohort. Using age distribution of LoF variants and 2 measures of mutational constraint, LOEUF (“loss-of-function observed/expected upper bound fraction”) and pLI (“probability of being loss-of-function intolerance”), we evaluated the pathogenicity, tolerance, and age-related penetrance of LoF mutations in specific genes associated with IBMF syndromes. This analysis led to insights into rare IBMF diseases, including syndromes associated with DHX34, MDM4, RAD51, SRP54, and WIPF1. Our results provide an important population-based framework for the interpretation of LoF variant pathogenicity in rare and emerging IBMF syndromes.

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“…As Slamf1 is a gene related to the more undifferentiated LT-HSCs (Beerman et al, 2010), it seems that this type of HSCs could be less active at the mRNA level in females than in males at P30 and P120. The differences in Gata2, together with the changes observed in Slamf1 could mean that female HSCs are more actively entering the cell cycle and differentiating than their male counterparts at P30, P50, and P120 (Rodrigues et al, 2012;Hirabayashi et al, 2017), suggesting different transcriptional processes for Figure 2 Relative expression values of Ly6a (Sca-1), Slamf1, Gata2, Id1, Ikzf1, and Cebpa mRNA expression levels in peripheral blood analyzed by RT-PCR. Males are represented using light gray bars, while females are represented with dark gray bars.…”

Section: Resultsmentioning

confidence: 99%

Comparative study of hematopoietic stem and progenitor cells between sexes in mice under physiological conditions along time

Gasco

Rando

Zaragoza

et al. 2017

Cell Biology International

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Hematopoietic stem and progenitor cells (HSPCs) are attractive targets in regenerative medicine, although the differences in their homeostatic maintenance between sexes along time are still under debate. We accurately monitored hematopoietic stem cells (HSCs), common lymphoid progenitors (CLPs), and common myeloid progenitors (CMPs) frequencies by flow cytometry, by performing serial peripheral blood extractions from male and female B6SJL wild-type mice and found no significant differences. Only modest differences were found in the gene expression profile of Slamf1 and Gata2. Our findings suggest that both sexes could be used indistinctly to perform descriptive studies in the murine hematopoietic system, especially for flow cytometry studies in peripheral blood. This would allow diminishing the number of animals needed for the experimental procedures. In addition, the use of serial extractions in the same animals drastically decreases the number of animals needed.

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Heterogeneity of GATA2-related myeloid neoplasms

Cited by 44 publications

References 44 publications

Germline predisposition in myeloid neoplasms: Unique genetic and clinical features of GATA2 deficiency and SAMD9/SAMD9L syndromes

Germline predisposition in myeloid neoplasms: Unique genetic and clinical features of GATA2 deficiency and SAMD9/SAMD9L syndromes

Human mutational constraint as a tool to understand biology of rare and emerging bone marrow failure syndromes

Comparative study of hematopoietic stem and progenitor cells between sexes in mice under physiological conditions along time

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