Haematopoietic and immune defects associated with GATA2 mutation

Abstract

SummaryHeterozygous familial or sporadic GATA2 mutations cause a multifaceted disorder, encompassing susceptibility to infection, pulmonary dysfunction, autoimmunity, lymphoedema and malignancy. Although often healthy in childhood, carriers of defective GATA2 alleles develop progressive loss of mononuclear cells (dendritic cells, monocytes, B and Natural Killer lymphocytes), elevated FLT3 ligand, and a 90% risk of clinical complications, including progression to myelodysplastic syndrome (MDS) by 60 years of age. Premature death may occur from childhood due to infection, pulmonary dysfunction, solid malignancy and MDS/acute myeloid leukaemia. GATA2 mutations include frameshifts, amino acid substitutions, insertions and deletions scattered throughout the gene but concentrated in the region encoding the two zinc finger domains. Mutations appear to cause haplo-insufficiency, which is known to impair haematopoietic stem cell survival in animal models. Management includes genetic counselling, prevention of infection, cancer surveillance, haematopoietic monitoring and, ultimately, stem cell transplantation upon the development of MDS or another lifethreatening complication.

The genomics of inherited bone marrow failure: from mechanism to the clinic

“…It is highly expressed in haematopoietic stem cells, multipotent haematopoietic progenitors, erythroid precursors, megakaryocytes, eosinophils and mast cells. GATA2 is required for proliferation and survival of early haematopoietic cells and mast cell formation, but dispensable for the erythroid and myeloid terminal differentiation (Collin et al , ).…”

Exploration of prognosis-related microRNA and transcription factor co-regulatory networks across cancer types

“…The two modules comprised the common regulators MYC and GATA2 (Fig S6), and the elements contained in the two modules are closely related to cancer progression. Amplification and overexpression of MYC are related to CXSCC progression and GATA2 mutations cause a multifaceted disorder [40,41].In the first module, GATA2 regulates both hsa-mir-30e and the target genes IL1A and ITGA5, with the hsa-mir-30e repressing the target genes. The target IL1A can promote tumour growth, invasion and migration [42] and the ITGA5 expression is induced in transformed epithelial cells during epithelial to mesenchymal transition (EMT) process which fuels metastasis by endowing cells with enhanced migratory and invasive potential [43][44][45].…”

Can somatic GATA2 mutation mimic germ line GATA2 mutation?

“…Twenty-five percent of sPAP patients have germ line GATA2 mutations, and one-fifth of germ line GATA2-mutated individuals develop PAP. 1,3,9,10 We report the first case of a patient with proven acquired/somatic GATA2 mutation who developed typical immunodeficiency features of germ line GATA2 mutation, including monocytopenia, probable mycobacterial infection, and PAP, on a background of MPN/MDS. All data and samples were collected after informed consent in accordance with the Declaration of Helsinki.…”

“…GATA2 is a zinc-finger transcription factor integral to hemopoietic stem cell regulation, mononuclear development, and alveolar macrophage activity. 1 Heterozygous germ line GATA2 mutations are associated with mycobacterial infection, monocytopenia, and deficiency of B/natural killer cells, and pulmonary alveolar proteinosis (PAP). GATA2 mutations confer a 90% lifetime risk of developing myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) with mutations detected in 7% to 15% of MDS in young adults and children.…”