Journal Article

Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia

Timms, Andrew E, Brown, Anna L, Lin, Ming, Hahn, Christopher N, Babic, Milena, Lewis, Ian D, Escher, Robert, Carmagnac, Amandine, Bardy, Peter G, Li, Xiao-Chun, Kok, Chung H, Gagliardi, Lucia, To, L Bik, Scott, Hamish S, Carmichael, Catherine L, Brautigan, Peter J, D'Andrea, Richard J, Chong, Chan-Eng, Butcher, Carolyn M, Friend, Kathryn L, Ekert, Paul G, Suthers, Graeme K, Altree, Meryl, Wilkins, Ella J, Lee, Young K, Moore, Sarah, Horwitz, Marshall S, Storek, Jan

2011

Overview

Hamish Scott and colleagues report that germline mutations in GATA2 segregate with myelodysplastic syndrome and acute myeloid leukemia in four pedigrees. The resulting alterations occur in a conserved zinc finger DNA-binding domain of GATA2. We report the discovery of GATA2 as a new myelodysplastic syndrome (MDS)-acute myeloid leukemia (AML) predisposition gene. We found the same, previously unidentified heterozygous c.1061C>T (p.Thr354Met) missense mutation in the GATA2 transcription factor gene segregating with the multigenerational transmission of MDS-AML in three families and a GATA2 c.1063_1065delACA (p.Thr355del) mutation at an adjacent codon in a fourth MDS family. The resulting alterations reside within the second zinc finger of GATA2, which mediates DNA-binding and protein-protein interactions. We show differential effects of the mutations on the transactivation of target genes, cellular differentiation, apoptosis and global gene expression. Identification of such predisposing genes to familial forms of MDS and AML is critical for more effective diagnosis and prognosis, counseling, selection of related bone marrow transplant donors and development of therapies.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 631/208/727/2000 / 631/208/737 / 692/699/67/1990/1673 / 692/699/67/1990/283/1897 / Agriculture / Amino Acid Sequence / Animal Genetics and Genomics / Animals / Biological and medical sciences / Biomedical and Life Sciences / Biomedicine / Bone marrow / Cancer Research / Cell Differentiation / Cell Proliferation / Chlorocebus aethiops / Chromosome Mapping / COS Cells / DNA, Complementary / Female / Fundamental and applied biological sciences. Psychology / GATA2 Transcription Factor - genetics / GATA2 Transcription Factor - metabolism / Gene Function / Gene mutations / Genetic aspects / Genetic Predisposition to Disease / Genetics of eukaryotes. Biological and molecular evolution / Haplotypes / Health aspects / HEK293 Cells / Hematologic and hematopoietic diseases / Human Genetics / Humans / letter / Leukemia / Leukemia, Myeloid, Acute - genetics / Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis / Male / Medical sciences / Molecular Sequence Data / Mutation / Myelodysplastic syndromes / Myelodysplastic Syndromes - genetics / Pedigree / Plasmids / Polymorphism, Single Nucleotide / Proteins / Quantitative Trait, Heritable / Risk factors