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Chronic myeloproliferative neoplasms

ASXL1/EZH2 mutations promote clonal expansion of neoplastic HSC and impair erythropoiesis in PMF

Leukemia volume 33, pages 99–109 (2019)Cite this article

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Abstract

Primary myelofibrosis (PMF) is a hematopoietic stem cell (HSC) disease, characterized by aberrant differentiation of all myeloid lineages and profound disruption of the bone marrow niche. PMF samples carry several mutations, but their cell origin and hierarchy in regulating the different waves of clonal and aberrant myeloproliferation from the prime HSC compartment is poorly understood. Genotyping of >2000 colonies from CD133+HSC and progenitors from PMF patients confirmed the complex genetic heterogeneity within the neoplastic population. Notably, mutations in chromatin regulators ASXL1 and/or EZH2 were identified as the first genetic lesions, preceding both JAK2-V617F and CALR mutations, and are thus drivers of clonal myelopoiesis in a PMF subset. HSC from PMF patients with double ASXL1/EZH2 mutations exhibited significantly higher engraftment in immunodeficient mice than those from patients without histone modifier mutations. EZH2 mutations correlate with aberrant erythropoiesis in PMF patients, exemplified by impaired maturation and cell cycle arrest of erythroid progenitors. These data underscore the importance of post-transcriptional modifiers of histones in neoplastic stem cells, whose clonal growth sustains aberrant myelopoiesis and expansion of pre-leukemic clones in PMF.

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Acknowledgements

The authors would like to thank Laura Montanus, Marla Wobbe, Roman Kanke and Martin Wichmann for their contribution to PCR and sequencing experiments and the personnel of the Core Facility in University Medical Center Hamburg Eppendorf for their assistance in FACS experiments. We thank Dr. Robert Geffers and Dr. Michael Jarek from the Genome Analytics Group, Helmholtz Centre for Infection Research, Braunschweig, Germany for next-generation sequencing services.

This work was supported from grants of the European Hematology Association, the José Carreras Leukaemia Foundation and Else Kröner-Fresenius-Foundation to IT and grants from the German Federal Ministry of Education and Research grant 01EO0802 (IFB-Tx) and from DFG grants HE 5240/5-1 and HE 5240/6-1 to MH.

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Authors and Affiliations

  1. Department for Stem Cell Transplantation, University Medical Center Hamburg – Eppendorf, Hamburg, Germany

    Ioanna Triviai, Silke Zeschke, Jan Rentel, Theo Scherer, Carol Stocking & Nicolaus Kröger

  2. Computational BioMedicine Laboratory (CBML), Institute of Computer Science (ICS), Foundation for Research and Technology Hellas (FORTH), Heraklion, Hellas, Greece

    Marios Spanakis

  3. Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany

    Razif Gabdoulline, Victoria Panagiota, Felicitas Thol & Michael Heuser

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  1. Ioanna Triviai
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Correspondence to Ioanna Triviai.

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Triviai, I., Zeschke, S., Rentel, J. et al. ASXL1/EZH2 mutations promote clonal expansion of neoplastic HSC and impair erythropoiesis in PMF. Leukemia 33, 99–109 (2019). https://doi.org/10.1038/s41375-018-0159-0

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