C/EBPÎ± and GATA-2 Mutations Induce Bilineage Acute Erythroid Leukemia through Transformation of a Neomorphic Neutrophil-Erythroid Progenitor.

Cancer Cell. 2020 May 11;37(5):690-704.e8. Epub 2020 Apr 23

Cristina Di Genua ¹ , Simona Valletta ¹ , Mario Buono ¹ , Bilyana Stoilova ² , Connor Sweeney ² ,

Cristina Di Genua ¹ , Simona Valletta ¹ , Mario Buono ¹ , Bilyana Stoilova ² , Connor Sweeney ² , Alba Rodriguez-Meira ¹ , Amit Grover ¹ , Roy Drissen ¹ , Yiran Meng ¹ , Ryan Beveridge ¹ , Zahra Aboukhalil ² , Dimitris Karamitros ² , Mirjam E Belderbos ³ , Leonid Bystrykh ⁴ , Supat Thongjuea ⁵ , Paresh Vyas ² , Claus Nerlov ⁶

+ et al

Author information

¹ MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK.
² MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK; NIHR Oxford Biomedical Research Center, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.
³ Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, the Netherlands.
⁴ European Research Institute for the Biology of Ageing, University Medical Center Groningen, 9713 AV Groningen, the Netherlands.
⁵ MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK; MRC WIMM Centre for Computational Biology, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK; NIHR Oxford Biomedical Research Center, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DU, UK.
⁶ MRC Molecular Haematology Unit, MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK. Electronic address: claus.nerlov@imm.ox.ac.uk.

摘要

Acute erythroid leukemia (AEL) commonly involves both myeloid and erythroid lineage transformation. However, the mutations that cause AEL and the cell(s) that sustain the bilineage leukemia phenotype remain unknown. We here show that combined biallelic Cebpa and Gata2 zinc finger-1 (ZnF1) mutations cooperatively induce bilineage AEL, and that the major leukemia-initiating cell (LIC) population has a neutrophil-monocyte progenitor (NMP) phenotype. In pre-leukemic NMPs Cebpa and Gata2 mutations synergize by increasing erythroid transcription factor (TF) expression and erythroid TF chromatin access, respectively, thereby installing ectopic erythroid potential. This erythroid-permissive chromatin conformation is retained in bilineage LICs. These results demonstrate that synergistic transcriptional and epigenetic reprogramming by leukemia-initiating mutations can generate neomorphic pre-leukemic progenitors, defining the lineage identity of the resulting leukemia.

KEYWORDS: CEBPA, GATA2, acute erythroid leukemia, acute myeloid leukemia, chromatin accessibility, leukemia-initiating cell, lineage priming, oncogene co-operation

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