GATA2 deficiency and MDS/AML: Experimental strategies for disease modelling and future therapeutic prospects

Abstract

The importance of predisposition to leukaemia in clinical practice is being increasingly recognized. This is emphasized by the establishment of a novel WHO disease category in 2016 called "myeloid neoplasms with germline predisposition". A major syndrome within this group is GATA2 deficiency, a heterogeneous immunodeficiency syndrome with a very high lifetime risk to develop myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). GATA2 deficiency has been identified as the most common hereditary cause of MDS in adolescents with monosomy 7. Allogenic haematopoietic stem cell transplantation is the only curative option; however, chances of survival decrease with progression of immunodeficiency and MDS evolution. Penetrance and expressivity within families carrying GATA2 mutations is often variable, suggesting that co-operating extrinsic events are required to trigger the disease. Predictive tools are lacking, and intrafamilial heterogeneity is poorly understood; hence there is a clear unmet medical need. On behalf of the ERAPerMed GATA2 HuMo consortium, in this review we describe the genetic, clinical, and biological aspects of familial GATA2-related MDS, highlighting the importance of developing robust disease preclinical models to improve early detection and clinical decision-making of GATA2 carriers.

Haemophagocytic lymphohistiocytosis caused by GATA2 deficiency: a report on three patients

“…GATA2 deficiency causes heterogeneous abnormalities, as indicated by haematological, immunological, and dermatological findings. GATA2 deficiency syndromes include cellular immune deficiency disorders, namely, MonoMac (monocytopenia and Mycobacterium infection) and Emberger syndrome (myelodysplasia and lymphedema); dendritic cell, monocyte, B and NK lymphocyte (DCML) deficiency; and myeloid malignancies and are mainly associated with familial and primary paediatric MDS and acute myeloid leukemia (AML) [8]. Even within the same family, the age at which symptoms appear can vary greatly, from early childhood to late adulthood.…”

Epigenome profiling reveals aberrant DNA methylation signature in GATA2 deficiency

“…GATA2 deficiency is a complex multi-system disorder with high risk of developing myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) with a nearly complete lifetime penetrance. 1 , 2 GATA2 carriers show a highly variable expressivity, with some individuals developing early-onset MDS, while others remain asymptomatic throughout life. Although no prognostic biomarkers exist, it is likely that both cooperating genetic and epigenetic drivers shape the course of the disease.…”