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

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. D'Andrea; Marshall S. Horwitz; Hamish S. Scott

doi:10.1038/ng.913

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

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 StorekSarah Moore, Meryl Altree, Robert Escher, Peter G. Bardy, Graeme K. Suthers, Richard J. D'Andrea, Marshall S. Horwitz, Hamish S. Scott

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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.

Original language	English
Pages (from-to)	1012-1019
Number of pages	8
Journal	Nature Genetics
Volume	43
Issue number	10
DOIs	https://doi.org/10.1038/ng.913
Publication status	Published or Issued - Oct 2011
Externally published	Yes

ASJC Scopus subject areas

Genetics

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Hahn, C. N., Chong, C. E., Carmichael, C. L., Wilkins, E. J., Brautigan, P. J., Li, X. C., Babic, M., Lin, M., Carmagnac, A., Lee, Y. K., Kok, C. H., Gagliardi, L., Friend, K. L., Ekert, P. G., Butcher, C. M., Brown, A. L., Lewis, I. D., To, L. B., Timms, A. E., ... Scott, H. S. (2011). Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia. Nature Genetics, 43(10), 1012-1019. https://doi.org/10.1038/ng.913

@article{ecc1b39be80c4b17a30ea97aa33c8968,

title = "Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia",

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.",

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

note = "Funding Information: 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.).",

year = "2011",

month = oct,

doi = "10.1038/ng.913",

language = "English",

volume = "43",

pages = "1012--1019",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "10",

}

Hahn, CN, Chong, CE, Carmichael, CL, Wilkins, EJ, Brautigan, PJ, Li, XC, Babic, M, Lin, M, Carmagnac, A, Lee, YK, Kok, CH, Gagliardi, L, Friend, KL, Ekert, PG, Butcher, CM, Brown, AL, Lewis, ID, To, LB, Timms, AE, Storek, J, Moore, S, Altree, M, Escher, R, Bardy, PG, Suthers, GK, D'Andrea, RJ, Horwitz, MS & Scott, HS 2011, 'Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia', Nature Genetics, vol. 43, no. 10, pp. 1012-1019. https://doi.org/10.1038/ng.913

TY - JOUR

T1 - Heritable GATA2 mutations associated with familial myelodysplastic syndrome and acute myeloid leukemia

AU - Hahn, Christopher N.

AU - Chong, Chan Eng

AU - Carmichael, Catherine L.

AU - Wilkins, Ella J.

AU - Brautigan, Peter J.

AU - Li, Xiao Chun

AU - Babic, Milena

AU - Lin, Ming

AU - Carmagnac, Amandine

AU - Lee, Young K.

AU - Kok, Chung H.

AU - Gagliardi, Lucia

AU - Friend, Kathryn L.

AU - Ekert, Paul G.

AU - Butcher, Carolyn M.

AU - Brown, Anna L.

AU - Lewis, Ian D.

AU - To, L. Bik

AU - Timms, Andrew E.

AU - Storek, Jan

AU - Moore, Sarah

AU - Altree, Meryl

AU - Escher, Robert

AU - Bardy, Peter G.

AU - Suthers, Graeme K.

AU - D'Andrea, Richard J.

AU - Horwitz, Marshall S.

AU - Scott, Hamish S.

N1 - Funding Information: 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.).

PY - 2011/10

Y1 - 2011/10

N2 - 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.

AB - 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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U2 - 10.1038/ng.913

DO - 10.1038/ng.913

M3 - Article

C2 - 21892162

AN - SCOPUS:80053383273

SN - 1061-4036

VL - 43

SP - 1012

EP - 1019

JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -

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

Abstract

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