Myelodysplastic Syndrome Due to Somatic GATA1 Mutation.

Inappropriate hematopoietic differentiation resulting in trilineage dysplasia is a diagnostic hallmark of myelodysplastic syndrome (MDS). Understanding the molecular basis of MDS will not only shed insight into this common hematological disease, but also Acute Myeloid Leukemia (as MDS often progresses to AML) and normal hematopoiesis. The genetic basis of MDS is unclear and in particular the role of deregulated transcription factor activity, which is often seen in AML, has not been clearly defined. For the first time we describe a novel somatic GATA1 mutation in a 13-year-old boy with MDS who has 10-year history of anemia, neutropenia, moderate thrombocytopenia, bone pain and hepatomegaly. Bone marrow biopsy demonstrated trilineage dysplasia with a normal karyotype of bone marrow mononuclear cells. Sequence analysis showed an A to G mutation in the X-linked GATA1 gene at residue 598 in exon 4 in platelets and bone marrow mononuclear cell cDNA. The mutation was also detected in genomic DNA from purified myeloid progenitors but not peripheral blood leucocytes. This discrepancy may be due to selection of peripheral blood leucocytes that do not carry the GATA1 mutation. The mutation was also not seen in skin fibroblasts. The predicted amino acid substitution E200G is located in a highly conserved residue at the beginning of the N-terminal zinc finger (Nf). This did not perturb DNA binding to GATA sites by EMSA analysis nor reduce interaction with FOG1. Importantly, immunoblot analysis of the patient’s platelets showed strongly reduced protein levels of GATA1, normal FOG1 and increased RUNX1. The index case had an increased Ivy bleeding time (>15 min) and a significant prolongation of the PFA-100 occlusion time (collagen/ADP and collagen/epinephrine). Platelet ATP secretion and platelet aggregation (epinephrine, ADP and U46) were decreased compared to control platelets. In contrast to patients with an inherited GATA1 mutation, the platelet phenotype in the MDS patient is completely different. Platelets from the patient are smaller in size (MPV 8.6fL) and electron microscopy revealed a markedly reduced number of dense granules. His platelets have a normal GPIbα expression and normal ristocetin-induced platelet agglutination. The previously described patients with inherited Nf GATA1 mutations (D218G GATA1 Blood,2001,98,85) have giant platelets with characteristic membrane complexes and reduced GPIbα expression with abnormal ristocetin-induced platelet agglutination. Further study of the index patient will provide important detailed insight into GATA1 function and help unravel how perturbed activity of key myeloid transcription factors results in MDS.