Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors.,Cancer Cell

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Ezh2 and Runx1 Mutations Collaborate to Initiate Lympho-Myeloid Leukemia in Early Thymic Progenitors.
Cancer Cell ( IF 50.3 ) Pub Date : 2018-02-12 , DOI: 10.1016/j.ccell.2018.01.006
Christopher A G Booth ₁ , Nikolaos Barkas ₁ , Wen Hao Neo ₁ , Hanane Boukarabila ₁ , Elizabeth J Soilleux ₂ , George Giotopoulos ₃ , Noushin Farnoud ₄ , Alice Giustacchini ₅ , Neil Ashley ₁ , Joana Carrelha ₁ , Lauren Jamieson ₁ , Deborah Atkinson ₁ , Tiphaine Bouriez-Jones ₁ , Rab K Prinjha ₆ , Thomas A Milne ₇ , David T Teachey ₈ , Elli Papaemmanuil ₄ , Brian J P Huntly ₃ , Sten Eirik W Jacobsen ₉ , Adam J Mead ₁₀

Affiliation

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.
Division of Cellular and Molecular Pathology, Department of Pathology, University of Cambridge, Cambridge, UK.
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.
Center for Molecular Oncology, Center for Heme Malignancies and Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
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.
Epigenetics DPU, Oncology and Immuno-Inflammation Therapy Area Units, GlaxoSmithKline, Stevenage, UK.
MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford OX3 9DS, UK.
Division of Oncology, Children's Hospital of Philadelphia and Department of Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
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.
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.

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.

中文翻译：

Ezh2和Runx1突变协作以在早期胸腺祖细胞中引发淋巴-淀粉样细胞白血病。

淋巴-髓样受限的早期胸腺祖细胞（ETP）被认为是ETP白血病的起源细胞，ETP白血病是一种与EZH2和RUNX1失活突变频繁并存并组成性激活信号通路突变相关的耐治疗性白血病。在小鼠模型中，我们证明了针对早期淋巴样祖细胞的Ezh2和Runx1失活导致白血病前ETP的显着扩展，显示ETP白血病的转录特征。RAS信号通路突变（Flt3-ITD）的添加会导致侵袭性白血病共表达髓样和淋巴样基因，这些基因可以通过扩展的ETP建立并在体内传播。小鼠和人类ETP白血病在体外和体内均显示出对BET抑制的敏感性，

更新日期：2018-02-13

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