Heritable GATA2 Mutations Associated with Familial Myelodysplastic Syndrome and Acute Myeloid Leukemia

Overview

Journal Nat Genet

Specialty Genetics

Date 2011 Sep 6

PMID 21892162

Citations 302

Authors

Christopher N Hahn

Chan-Eng Chong

Catherine L Carmichael

Ella J Wilkins

Peter J Brautigan

Xiao-Chun Li

Milena Babic

Ming Lin

Amandine Carmagnac

Young K Lee

Chung H Kok

Lucia Gagliardi

Kathryn L Friend

Paul G Ekert

Carolyn M Butcher

Anna L Brown

Ian D Lewis

L Bik To

Andrew E Timms

Jan Storek

Sarah Moore

Meryl Altree

Robert Escher

Peter G Bardy

Graeme K Suthers

Richard J DAndrea

Marshall S Horwitz

Hamish S Scott

Affiliations

Soon will be listed here.

Abstract

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.

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