Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors

Christopher A G Booth; Nikolaos Barkas; Wen Hao Neo; Hanane Boukarabila; Elizabeth J Soilleux; George Giotopoulos; Noushin Farnoud; Alice Giustacchini; Neil Ashley; Joana Carrelha; Lauren Jamieson; Deborah Atkinson; Tiphaine Bouriez-Jones; Rab K Prinjha; Thomas A Milne; David T Teachey; Elli Papaemmanuil; Brian J P Huntly; Sten Eirik W Jacobsen; Adam J Mead

doi:10.1016/j.ccell.2018.01.006

Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors

Cancer Cell. 2018 Feb 12;33(2):274-291.e8. doi: 10.1016/j.ccell.2018.01.006.

Authors

Christopher A G Booth¹, Nikolaos Barkas¹, Wen Hao Neo¹, Hanane Boukarabila¹, Elizabeth J Soilleux², George Giotopoulos³, Noushin Farnoud⁴, Alice Giustacchini⁵, Neil Ashley¹, Joana Carrelha¹, Lauren Jamieson¹, Deborah Atkinson¹, Tiphaine Bouriez-Jones¹, Rab K Prinjha⁶, Thomas A Milne⁷, David T Teachey⁸, Elli Papaemmanuil⁴, Brian J P Huntly³, Sten Eirik W Jacobsen⁹, Adam J Mead¹⁰

Affiliations

¹ Haematopoietic Stem Cell Biology Laboratory, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK.
² Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge, UK.
³ Wellcome Trust-MRC Cambridge Stem Cell Institute, Cambridge, UK; Department of Haematology, University of Cambridge, Cambridge, UK; Cambridge Institute for Medical Research, Cambridge Biomedical Campus, Hills Road, Cambridge CB2 0XY, UK.
⁴ Center for Molecular Oncology, Center for Heme Malignancies and Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
⁵ Haematopoietic Stem Cell Biology Laboratory, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK; Department of Cell and Developmental Biology, University College London, London WC1E 6BT, UK.
⁶ Epigenetics DPU, Oncology and Immuno-Inflammation Therapy Area Units, GlaxoSmithKline, Stevenage, UK.
⁷ MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK.
⁸ Division of Oncology, Children's Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
⁹ Haematopoietic Stem Cell Biology Laboratory, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK; Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, SE-141 86 Stockholm, Sweden; Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden. Electronic address: sten.jacobsen@imm.ox.ac.uk.
¹⁰ Haematopoietic Stem Cell Biology Laboratory, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK; MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK; NIHR Biomedical Research Centre, Churchill Hospital, Oxford OX3 7LE, UK. Electronic address: adam.mead@imm.ox.ac.uk.

PMID: 29438697
DOI: 10.1016/j.ccell.2018.01.006

Abstract

Lympho-myeloid restricted early thymic progenitors (ETPs) are postulated to be the cell of origin for ETP leukemias, a therapy-resistant leukemia associated with frequent co-occurrence of EZH2 and RUNX1 inactivating mutations, and constitutively activating signaling pathway mutations. In a mouse model, we demonstrate that Ezh2 and Runx1 inactivation targeted to early lymphoid progenitors causes a marked expansion of pre-leukemic ETPs, showing transcriptional signatures characteristic of ETP leukemia. Addition of a RAS-signaling pathway mutation (Flt3-ITD) results in an aggressive leukemia co-expressing myeloid and lymphoid genes, which can be established and propagated in vivo by the expanded ETPs. Both mouse and human ETP leukemias show sensitivity to BET inhibition in vitro and in vivo, which reverses aberrant gene expression induced by Ezh2 inactivation.

Keywords: BET inhibition; EZH2; FLT3-ITD; RUNX1; early thymic progenitor leukemia; early thymic progenitors; leukemia propagating cells; leukemic stem cells.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Core Binding Factor Alpha 2 Subunit / genetics*
Enhancer of Zeste Homolog 2 Protein / genetics*
Gene Expression Regulation, Leukemic
Leukemia, Myeloid, Acute / genetics*
Mice, Knockout
Mutation / genetics*
Myeloid Cells / metabolism
Signal Transduction / genetics
Stem Cells

Substances

Core Binding Factor Alpha 2 Subunit
RUNX1 protein, human
Runx1 protein, mouse
EZH2 protein, human
Enhancer of Zeste Homolog 2 Protein
Ezh2 protein, mouse

Abstract

Publication types

MeSH terms

Substances

Grants and funding