Germline mutation in GATA2 can lead to GATA2 deficiency characterized by a complex multi-system disorder that can present with many manifestations including variable cytopenias, bone marrow failure, myelodysplastic syndrome/acute myeloid leukemia (MDS/AML), and severe immunodeficiency.
GATA2 haploinsufficiency is implicated in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), and GATA2 overexpression portends a poor prognosis for AML.
Heterozygous GATA-2 germline mutations are associated with overlapping clinical manifestations termed GATA-2 deficiency, characterized by immunodeficiency and predisposition to myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).
Guanine-adenine-thymine-adenine 2 (GATA2) mutated disorders include the recently described MonoMAC syndrome (Monocytopenia and Mycobacterium avium complex infections), DCML (dendritic cell, monocyte, and lymphocyte deficiency), familial MDS/AML (myelodysplastic syndrome/acute myeloid leukemia) (myeloid neoplasms), congenital neutropenia, congenital lymphedema (Emberger's syndrome), sensorineural deafness, viral warts, and a spectrum of aggressive infections seen across all age groups.
Two previously reported adult GATA2-deficient patients died from severe H1N1 IAV infection; GATA2 deficiency may predispose to life-threatening influenza in adulthood.
Thus, allogeneic hematopoietic stem cell transplant results in reconstitution of immunologic function and cure of EBV-associated malignancy in MonoMAC/GATA2 deficiency.
Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature.
Heterozygous germline mutations in GATA2 have been initially associated with several clinical entities that are now collectively defined as GATA2 deficiency.
Mutational sensitization to stress that instigates hematopoietic failure constitutes a paradigm for GATA-2 deficiency syndrome and other contexts of GATA-2-dependent pathogenesis.
GATA2 mutations have been identified in various diseases, such as MonoMAC syndrome, Emberger syndrome, familial myelodysplastic syndrome, acute myeloid leukaemia and dendritic cell, monocyte, B-cell and natural killer-cell deficiency.
Because patients with GATA-2 deficiency syndrome could retain a wild-type copy of GATA-2, boosting residual wild-type GATA-2 activity may represent a novel therapeutic strategy for the disease.
Mean plasma levels of tumor necrosis factor α, interferon γ, and interferon gamma-induced protein 10 were higher in patients with GATA2 deficiency than in controls.
Somatic, heterozygous ASXL1 mutations were identified in 14/48 (29%) of patients with GATA2 deficiency, including four out of five patients who developed a proliferative chronic myelomonocytic leukemia.
In contrast to GATA2 deficiency, supplementation with miR-126 normalized vascular function and expression profiles of cytokines contributing to proangiogenic paracrine effects.
Surprisingly, MSC-specific GATA2 deficiency impairs the trabecularization and mechanical strength of bone, involving reduced MSC expression of the osteoclast inhibitor osteoprotegerin and increased osteoclast numbers.