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


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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Figure 1: Identification of new germline p.Thr354Met and p.Thr355del variants in the highly conserved zinc finger 2 domain of GATA2 that is associated with MDS-AML.
Figure 2: Subcellular localization and DNA binding properties of wild-type and mutant GATA2.
Figure 3: p.Thr354Met and Thr355del cause altered transactivation through target GATA2 response elements.
Figure 4: p.Thr354Met inhibits differentiation and apoptosis while allowing accumulation of cells in the presence of ATRA-induced differentiation.

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The authors would like to thank the families for their participation in our studies. Thanks also to J. Melo for provision of CML cell lines and R. Sharma for help with EMSA. Large-scale Sanger sequencing was performed by the Australian Genome Research Facility, which was established through the Commonwealth-funded Major National Research Facilities program. This work was supported by grants from the National Health and Medical Research Council of Australia (program grants 257501 (H.S.S.) and 219176 (H.S.S.), project grant 1002317 (C.N.H., R.J.D. and H.S.S.), fellowships 171601 (H.S.S.) and 461204 (H.S.S.), and a Dora Lush Postgraduate Award (C.L.C.)), Leukaemia Foundation of Australia (grant in aid to H.S.S. and a postdoctoral fellowship to C.L.C.), the Cancer Council of South Australia (H.S.S.) and MedVet Pty Ltd (H.S.S. and R.J.D.), Adelaide Scholarships International (scholarship to C.-E.C.) and US National Institutes of Health grant R01DK058161 (M.S.H.).

Author information

C.N.H., R.J.D., M.S.H. and H.S.S. managed the project. C.N.H., C.L.C., E.J.W., C.-E.C., P.J.B., X.-C.L., M.B., M.L., A.C., Y.K.L., C.M.B., K.L.F. and A.E.T. performed the experiments. C.H.K. and R.J.D. performed structural modeling, and C.N.H., C.H.K. and L.G. performed data analysis. L.B.T., M.A., J.S., P.G.B., G.K.S., R.J.D., M.S.H. and H.S.S. collected families with MDS and/or AML and provided clinical data and samples. R.E. and P.G.E. participated in experimental design and provided critical reagents. A.L.B., I.D.L., S.M. and L.B.T. provided sporadic AML samples and correlative clinical data. C.N.H., R.J.D., M.S.H. and H.S.S. wrote the manuscript.

Correspondence to Hamish S Scott.

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Supplementary Figures 1–8, Supplementary Tables 1–13 and Supplementary Note. (PDF 1327 kb)

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Hahn, C., Chong, C., Carmichael, C. et al. Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nat Genet 43, 1012–1017 (2011). https://doi.org/10.1038/ng.913

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