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

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

doi:10.1016/j.ccell.2020.03.022

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

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

Group Belderbos

Research output: Contribution to journal › Article › peer-review

18 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	690-704.e8
Journal	Cancer cell
Volume	37
Issue number	5
DOIs	https://doi.org/10.1016/j.ccell.2020.03.022
Publication status	Published - 11 May 2020

Keywords

Aged
Alleles
Animals
CCAAT-Enhancer-Binding Protein-alpha/genetics
Cell Differentiation
Cell Lineage
Cell Transformation, Neoplastic/genetics
Disease Models, Animal
Erythroid Precursor Cells/metabolism
Female
GATA1 Transcription Factor/genetics
GATA2 Transcription Factor/genetics
Humans
Leukemia, Erythroblastic, Acute/genetics
Male
Mice
Mice, Inbred C57BL
Middle Aged
Mutation
Neutrophils/metabolism
Zinc Fingers

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10.1016/j.ccell.2020.03.022

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Di Genua, C., Valletta, S., Buono, M., Stoilova, B., Sweeney, C., Rodriguez-Meira, A., Grover, A., Drissen, R., Meng, Y., Beveridge, R., Aboukhalil, Z., Karamitros, D., Belderbos, M. E., Bystrykh, L., Thongjuea, S., Vyas, P., & Nerlov, C. (2020). C/EBPα and GATA-2 Mutations Induce Bilineage Acute Erythroid Leukemia through Transformation of a Neomorphic Neutrophil-Erythroid Progenitor. Cancer cell, 37(5), 690-704.e8. https://doi.org/10.1016/j.ccell.2020.03.022

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title = "C/EBPα and GATA-2 Mutations Induce Bilineage Acute Erythroid Leukemia through Transformation of a Neomorphic Neutrophil-Erythroid Progenitor",

abstract = "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 = "Aged, Alleles, Animals, CCAAT-Enhancer-Binding Protein-alpha/genetics, Cell Differentiation, Cell Lineage, Cell Transformation, Neoplastic/genetics, Disease Models, Animal, Erythroid Precursor Cells/metabolism, Female, GATA1 Transcription Factor/genetics, GATA2 Transcription Factor/genetics, Humans, Leukemia, Erythroblastic, Acute/genetics, Male, Mice, Mice, Inbred C57BL, Middle Aged, Mutation, Neutrophils/metabolism, Zinc Fingers",

author = "{Di Genua}, Cristina and Simona Valletta and Mario Buono and Bilyana Stoilova and Connor Sweeney and Alba Rodriguez-Meira and Amit Grover and Roy Drissen and Yiran Meng and Ryan Beveridge and Zahra Aboukhalil and Dimitris Karamitros and Belderbos, {Mirjam E} and Leonid Bystrykh and Supat Thongjuea and Paresh Vyas and Claus Nerlov",

year = "2020",

month = may,

day = "11",

doi = "10.1016/j.ccell.2020.03.022",

language = "English",

volume = "37",

pages = "690--704.e8",

journal = "Cancer cell",

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Di Genua, C, Valletta, S, Buono, M, Stoilova, B, Sweeney, C, Rodriguez-Meira, A, Grover, A, Drissen, R, Meng, Y, Beveridge, R, Aboukhalil, Z, Karamitros, D, Belderbos, ME, Bystrykh, L, Thongjuea, S, Vyas, P & Nerlov, C 2020, 'C/EBPα and GATA-2 Mutations Induce Bilineage Acute Erythroid Leukemia through Transformation of a Neomorphic Neutrophil-Erythroid Progenitor', Cancer cell, vol. 37, no. 5, pp. 690-704.e8. https://doi.org/10.1016/j.ccell.2020.03.022

TY - JOUR

T1 - C/EBPα and GATA-2 Mutations Induce Bilineage Acute Erythroid Leukemia through Transformation of a Neomorphic Neutrophil-Erythroid Progenitor

AU - Di Genua, Cristina

AU - Valletta, Simona

AU - Buono, Mario

AU - Stoilova, Bilyana

AU - Sweeney, Connor

AU - Rodriguez-Meira, Alba

AU - Grover, Amit

AU - Drissen, Roy

AU - Meng, Yiran

AU - Beveridge, Ryan

AU - Aboukhalil, Zahra

AU - Karamitros, Dimitris

AU - Belderbos, Mirjam E

AU - Bystrykh, Leonid

AU - Thongjuea, Supat

AU - Vyas, Paresh

AU - Nerlov, Claus

PY - 2020/5/11

Y1 - 2020/5/11

N2 - 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.

AB - 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.

KW - Aged

KW - Alleles

KW - Animals

KW - CCAAT-Enhancer-Binding Protein-alpha/genetics

KW - Cell Differentiation

KW - Cell Lineage

KW - Cell Transformation, Neoplastic/genetics

KW - Disease Models, Animal

KW - Erythroid Precursor Cells/metabolism

KW - Female

KW - GATA1 Transcription Factor/genetics

KW - GATA2 Transcription Factor/genetics

KW - Humans

KW - Leukemia, Erythroblastic, Acute/genetics

KW - Male

KW - Mice

KW - Mice, Inbred C57BL

KW - Middle Aged

KW - Mutation

KW - Neutrophils/metabolism

KW - Zinc Fingers

UR - http://www.scopus.com/inward/record.url?scp=85084243791&partnerID=8YFLogxK

U2 - 10.1016/j.ccell.2020.03.022

DO - 10.1016/j.ccell.2020.03.022

M3 - Article

C2 - 32330454

SN - 1535-6108

VL - 37

SP - 690-704.e8

JO - Cancer cell

JF - Cancer cell

IS - 5

ER -

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

Abstract

Keywords

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