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Cytogenetics and molecular genetics

Chromosome 21 gain is dispensable for transient myeloproliferative disorder driven by a novel GATA1 mutation

Leukemia volume 34, pages 2503–2508 (2020)Cite this article

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Transient myeloproliferative disease (TMD) represents a complex disorder of fetal hematopoiesis including dyserythropoiesis and clonal proliferation of immature megakaryoblasts that manifests in ~10% of newborns with Down syndrome [1]. Its clinical course ranges from asymptomatic/mild, with no need of treatment, to life-threatening, when multiple organs are affected and urgent intervention is needed. However, the disease typically remits even without treatment upon the switch to adult-type hematopoiesis during the first months of life. Nevertheless, there is a high risk of progression into acute megakaryocytic leukemia (AMKL) during early childhood [1,2,3].

TMD results from the cooperation of trisomy 21 (tri21) and somatic mutations in the GATA1 gene [4]. So far, it has not been fully elucidated, which genes on chromosome 21 are essential for TMD development; candidates include RUNX1, ETS2, ERG (which all encode hematopoietic transcription factors, similarly to GATA1) and miR-125b-2 [5, 6]. It was shown, that tri21 leads to increased self-renewal of fetal hematopoietic stem cells and expansion of megakaryocytic progenitors, which results in the aberrant proliferation of megakaryoblasts upon acquisition of GATA1 mutations [6,7,8].

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Fig. 1: Characterization of novel mutations in the GATA1 and JAK1 genes found in the reported TMD patient and the morphology of his TMD blasts.
Fig. 2: In vitro analyses of functional impact of JAK1 F636del.

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Acknowledgements

The study was supported by the Charles University (grants GA UK No 86218, Primus/MED/28 and UNCE 204012), grants from the Czech Health Research Council (NV15-30626A and NV18-07-00430), by the project (Ministry of Health, Czech Republic) for conceptual development of research organization 00064203 (University Hospital Motol, Prague, Czech Republic), and by institutional funding from the IMG of the CAS (RVO 68378050). Research infrastructure was supported by Ministry of Education, Youth and Sports (NPU I no. LO1604 and LM2018132). Funding for this project was provided in part by an EHA Research Mobility Grant awarded by the European Hematology Association. We would like to thank Elena Vodickova for sharing her expertise on cell morphology.

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Authors and Affiliations

  1. CLIP-Childhood Leukaemia Investigation Prague, Prague, Czech Republic

    Julius Lukes Jr., Eliska Potuckova, Julia Starkova, Ester Mejstrikova, Meritxell Alberich-Jorda, Jan Zuna, Jan Trka & Marketa Zaliova

  2. Department of Paediatric Haematology and Oncology, Second Faculty of Medicine, Charles University, Prague, Czech Republic

    Julius Lukes Jr., Eliska Potuckova, Julia Starkova, Jan Stary, Ester Mejstrikova, Jan Zuna, Jan Trka & Marketa Zaliova

  3. Department of Hemato-Oncology, Institute of Molecular Genetics, Czech Academy of Sciences, Prague, Czech Republic

    Petr Danek & Meritxell Alberich-Jorda

  4. Pediatric Hematology and Oncology, Martin-Luther-University Halle-Wittenberg, Halle, Germany

    Oriol Alejo-Valle, Dirk Heckl & Jan-Henning Klusmann

  5. Institute of Parasitology, Biology Center, Czech Academy of Sciences, Ceske Budejovice, Prague, Czech Republic

    Ondrej Gahura

  6. University Hospital Motol, Prague, Czech Republic

    Jan Stary, Ester Mejstrikova, Jan Zuna, Jan Trka & Marketa Zaliova

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Contributions

MZ designed and led the study, JL, PD, OAV, EP and OG performed the experiments and analyzed the data, DH, JuS, JaS, EM, MAJ, JZ, JT and JHK provided patient material, data and technologies, all authors participated on data interpretation, JL and MZ wrote the manuscript, all authors revised the manuscript and approved the final version.

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Correspondence to Marketa Zaliova.

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Lukes, J., Danek, P., Alejo-Valle, O. et al. Chromosome 21 gain is dispensable for transient myeloproliferative disorder driven by a novel GATA1 mutation. Leukemia 34, 2503–2508 (2020). https://doi.org/10.1038/s41375-020-0769-1

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