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Characterisation of a compound in-cis GATA2 germline mutation in a pedigree presenting with myelodysplastic syndrome/acute myeloid leukemia with concurrent thrombocytopenia

Leukemia volume 29, pages 1795–1797 (2015)Cite this article

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Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) are haematological disorders that are characterised by the aberrant proliferation of abnormal myeloblasts in the bone marrow and the inability of these cells to differentiate into mature myeloid cells. Both are largely sporadic diseases; however, rare familial cases have been described. Predisposition genes identified for these disorders include those for the RUNX1 and CEBPA transcription factors, the telomere maintenance genes TERC and TERT and, most recently, the GATA2 transcription factor gene, and the SRP72 gene which has a role in protein translocation and processing.1, 2, 3, 4, 5 A range of GATA2 mutations associated with familial MDS/AML has been identified.2, 6, 7, 8 These mutations tend to cluster in zinc finger 2 (ZF2) of GATA2, a domain that has a role in both DNA binding and interaction with other proteins, such as the key myeloid transcription factor PU.1(ref. 9). Both loss-of-function (LOF) and gain-of-function (GOF) GATA2 mutations have been identified. Germline GATA2 mutations have also been reported in other associated disorders, including MonoMAC,10, 11 DCML deficiency12 and Emberger Syndrome.3

Gao et al.13 have recently reported a novel compound in-cis GATA2 mutation in an individual from a family presenting with MDS/AML with concurrent thrombocytopenia. The proband was a 50-year-old woman with a history of thrombocytopenia, who was subsequently diagnosed with AML. Her mother, siblings, children and sibling’s children all presented with thrombocytopenia, and her mother and maternal aunt presented with MDS. MDS/AML with concurrent thrombocytopenia is a phenotype normally associated with germline RUNX1 mutations, but has not been previously associated with GATA2 mutation.14 The two missense mutations reside in the ZF2 of GATA2 on adjacent codons (c.[1073C>A;1075T>G], p.[(Thr358Asn;Leu359Val)]; T358N/L359V), and represent the first example of in-cis germline mutations observed in GATA2. The L359V mutation has previously been identified in recurrent somatic (but not germline) CML progression from chronic phase to blast crisis, and has been shown to increase both the GATA2 transactivation activity and its ability to bind the GATA2 co-factor PU.1, resulting in PU.1 inhibition.15 The T358N mutation has not been previously identified, however, a very rare polymorphism at this position, resulting in T358I, has been documented in dbSNP (rs148942346) with no associated phenotype.

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Acknowledgements

This project was supported by grants from the NHMRC APP1002317 and APP1024215, and fellowship APP1023059.

Author Contributions

PJB, AJ performed transactivation assays and molecular modelling, and contributed to the writing of the manuscript. YL performed WEMSA assays. C-EC performed transactivation assays and molecular modelling. PV performed the transactivation assays. AET and MSH performed the molecular analysis. MK-H, CNH and HSS supervised the project and contributed to the experimental design. CNH and HSS finalised the writing of the manuscript.

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Author notes

  1. C N Hahn, P J Brautigan, C-E Chong and A Janssan: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Genetics and Molecular Pathology, SA Pathology, Adelaide, South Australia, Australia

    C N Hahn, P J Brautigan, C-E Chong, A Janssan, P Venugopal, Y Lee, M Klingler-Hoffmann & H S Scott

  2. Centre for Cancer Biology, SA Pathology and the University of South Australia, Adelaide, South Australia, Australia

    C N Hahn, P J Brautigan, C-E Chong, A Janssan, P Venugopal, Y Lee, M Klingler-Hoffmann & H S Scott

  3. School of Medicine, University of Adelaide, Adelaide, South Australia, Australia

    C N Hahn & H S Scott

  4. School of Biological Sciences, University of Adelaide, Adelaide, South Australia, Australia

    A Janssan, P Venugopal, M Klingler-Hoffmann & H S Scott

  5. Division of Health Sciences, School of Pharmacy and Medical Sciences, University of South Australia, Adelaide, South Australia, Australia

    Y Lee & H S Scott

  6. Department of Pathology, University of Washington School of Medicine, Seattle, WA, USA

    A E Tims & M S Horwitz

  7. Seattle Children's Research Institute, Seattle, WA, USA

    A E Tims

  8. ACRF Cancer Genomics Facility, Centre for Cancer Biology, SA Pathology, Adelaide, South Australia, Australia

    H S Scott

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  1. C N Hahn
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Correspondence to H S Scott.

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Hahn, C., Brautigan, P., Chong, CE. et al. Characterisation of a compound in-cis GATA2 germline mutation in a pedigree presenting with myelodysplastic syndrome/acute myeloid leukemia with concurrent thrombocytopenia. Leukemia 29, 1795–1797 (2015). https://doi.org/10.1038/leu.2015.40

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