GATA2 in Bone Marrow Failure

The syndrome now known as GATA2 haploinsufficiency had been published at least since the 1970s under different clinical guises. With the identification of the gene in 2011, GATA2 deficiency became the overarching diagnosis for a complex syndrome with acoustic, cutaneous, lymphatic, pulmonary, leukemic, hematologic and infectious manifestations. Arising in both spontaneous and autosomal dominant patterns, the genetics made it recognizable and diagnosable even before symptoms arose. Over the last several years it has become clear that GATA2 is a major contributor to: pediatric and adolescent MDS, AML in younger adults, some cases of ALL, severe genital HPV infection, disseminated mycobacterial infections, pulmonary alveolar proteinosis, pulmonary hypertension and is associated with a variety of solid tumors. Mutations with more profound effects on GATA2 expression (nonsense and deletions) appear to have a more severe phenotype than do intronic mutations that alter transcript level but not transcript integrity. These latter intronic mutations may be associated with later onset of disease and more variable penetrance. Elucidating the gene targets on which GATA2 works and which partners it engages will lead to important observations in the molecular genetics of hematopoietic control.

This variability of penetrance and expression is most apparent with the intronic mutations, in which whole generations may be relatively protected, presumably from genes in trans to GATA2 . An active search is on for these genes that appear to regulate GATA2 . One of the consequences of the variable penetrance of GATA2 deficiency is that it may be discordant within a family, allowing a false sense of security about use of a clinically well relative for bone marrow transplant donation. Hematopoietic stem cell transplantation is highly effective for cure of GATA2 deficiency. We have now done almost 40 transplants in GATA2 deficiency with high survival rates using related haploidentical donors, as well as with fully matched donors. The effects of transplantation are profound both in terms of hematopoietic and somatic results, including resolution of most HPV lesions, resolution of pulmonary alveolar proteinosis and resolution of pulmonary hypertension, when present. We have now encountered several cases of transplant from unexpectedly affected donors into a known GATA2, all of which have had poor outcomes. These cases reinforce the critical need for molecular confirmation of the GATA2 status of any related donor, regardless of lack of symptoms.

GATA2 deficiency is recently recognized but successful treatments have emerged alongside the science. Efforts to understand and allow for manipulation of GATA2 expression are underway.