We have recently identified germline GATA2 mutations in autosomal dominant familial myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML), and Emberger syndrome (primary lymphoedema with MDS/AML) caused by de novo mutation. Others also identified germline GATA2 mutations in Emberger syndrome, MonoMAC syndrome (also called DCML deficiency, an immunodeficiency with MDS/AML), revealing a diversity of clinical presentations.While the role of the GATA2 transcription factor in differentiation, proliferation and survival of haematopoietic stem cells and progenitor cells is well known, its role in lymphatic vascular development as suggested by the patients with primary lymphoedema is less well described. While all germline GATA2 mutations predispose heterozygous individuals to MDS/AML and immunodeficiency, the constellation of phenotypes present in individual patients may be a consequence of allele specific effects and/or modifier genes and/or or environmental interactions. Emberger syndrome mutations are predominantly nonsense, and frameshift mutations towards the N-terminus of the protein, as well as complete gene deletions. This suggests that complete haploinsufficiency or loss-of-function (LOF) of GATA2 is a key predisposing factor for lymphedema onset.
We have investigated the function of several GATA2 mutations present in the different haematopoietic malignancy, immunodeficiency and lymphoedema diseases. While most mutants demonstrated lower GATA consensus DNA binding and transactivation ability in vitro, there are allele specific differences that may offer biological explanations of the different clinical presentations. We are continuing to identify somatic genetic lesions that occur as this familial hematological malignancies progress. We have also recently identified predisposing mutations in another familial hematological malignancies (HMs). These studies have immediate and direct implications for affected families and are beneficial for counselling, family planning and, ultimately, choices of therapy. The genes responsible for familial HMs are also likely to be of considerable importance in sporadic HMs.