C/EBP alpha 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/EBP alpha 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^*

^*Corresponding author for this work

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

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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
Number of pages	23
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

BIALLELIC CEBPA MUTATIONS
ACUTE MYELOID-LEUKEMIA
TRANSCRIPTION FACTORS
PU.1 TRANSCRIPTION
READ ALIGNMENT
RNA-SEQ
CELL
EXPRESSION
DIFFERENTIATION
ERYTHROLEUKEMIA

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C/EBPα and GATA-2 Mutations Induce Bilineage Acute Erythroid Leukemia through Transformation of a Neomorphic Neutrophil-Erythroid ProgenitorFinal publisher's version, 5.21 MBLicence: CC BY

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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/EBP alpha 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

@article{c3d134770ebf485eb6441b480ce18698,

title = "C/EBP alpha 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 = "BIALLELIC CEBPA MUTATIONS, ACUTE MYELOID-LEUKEMIA, TRANSCRIPTION FACTORS, PU.1 TRANSCRIPTION, READ ALIGNMENT, RNA-SEQ, CELL, EXPRESSION, DIFFERENTIATION, ERYTHROLEUKEMIA",

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",

issn = "1535-6108",

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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/EBP alpha 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/EBP alpha 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 - BIALLELIC CEBPA MUTATIONS

KW - ACUTE MYELOID-LEUKEMIA

KW - TRANSCRIPTION FACTORS

KW - PU.1 TRANSCRIPTION

KW - READ ALIGNMENT

KW - RNA-SEQ

KW - CELL

KW - EXPRESSION

KW - DIFFERENTIATION

KW - ERYTHROLEUKEMIA

U2 - 10.1016/j.ccell.2020.03.022

DO - 10.1016/j.ccell.2020.03.022

M3 - Article

SN - 1535-6108

VL - 37

SP - 690-704.e8

JO - Cancer cell

JF - Cancer cell

IS - 5

ER -

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

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