GATA factor mutations in hematologic disease

Abstract

GATA family proteins play essential roles in development of many cell types, including hematopoietic, cardiac, and endodermal lineages. The first three factors, GATAs 1, 2, and 3, are essential for normal hematopoiesis, and their mutations are responsible for a variety of blood disorders. Acquired and inherited GATA1 mutations contribute to Diamond-Blackfan anemia, acute megakaryoblastic leukemia, transient myeloproliferative disorder, and a group of related congenital dyserythropoietic anemias with thrombocytopenia. Conversely, germ line mutations in GATA2 are associated with GATA2 deficiency syndrome, whereas acquired mutations are seen in myelodysplastic syndrome, acute myeloid leukemia, and in blast crisis transformation of chronic myeloid leukemia. The fact that mutations in these genes are commonly seen in blood disorders underscores their critical roles and highlights the need to develop targeted therapies for transcription factors. This review focuses on hematopoietic disorders that are associated with mutations in two prominent GATA family members, GATA1 and GATA2.

Figure 1.

GATA1 mutations in benign hematologic disorders often affect the function of N-terminal zinc finger. (A) The normal function of the N-finger is to bind DNA at complex GATA motifs and to recruit FOG1; together, GATA1 and FOG1 drive expression of numerous red cell and megakaryocyte (Mk) genes. (B) Mutations in the FOG1-binding face of GATA1 disrupt the protein-protein interaction and diminish the expression of target genes. (C) Mutations in the N-finger that reduce the affinity of GATA1 for DNA also suppress expression of GATA1 target genes. (D) Structural representation of mutants in the GATA1 N-finger (magenta). Residues that are mutated in these disorders are indicated as spheres. The positions of FOG1 (yellow, derived from the structure of the GATA1:FOG1 structure) and DNA (gray, inferred from the structure of the GATA1-DNA complex) are shown. The NMR structure of the N-finger of GATA1 confirms the localization of the mutations to the FOG-interacting (left) or DNA binding surface (right).

Figure 2.

Progression of myeloid leukemia in children with DS. GATA1 mutations commonly occur in utero as early as week 21 of gestation in hematopoietic progenitors with trisomy 21. The resulting TMD is initially polyclonal, with multiple distinct GATA1-mutant clones. The GATA1 mutational burden diminishes shortly after birth as the TMD resolves. Over the course of one to three years, a persistent GATA1-mutant clone may acquire a tertiary mutation, which leads to clonal expansion and acute megakaryocytic leukemia.