C/EBPγ deregulation results in differentiation arrest in acute myeloid leukemia

Meritxell Alberich-Jordà; Bas Wouters; Martin Balastik; Clara Shapiro-Koss; Hong Zhang; Annalisa DiRuscio; Hanna S. Radomska; Alexander K. Ebralidze; Giovanni Amabile; Min Ye; Junyan Zhang; Irene Lowers; Roberto Avellino; Ari Melnick; Maria E. Figueroa; Peter J.M. Valk; Ruud Delwel; Daniel G. Tenen

doi:10.1172/JCI65102

C/EBPγ deregulation results in differentiation arrest in acute myeloid leukemia

Meritxell Alberich-Jordà
, Bas Wouters
, Martin Balastik
, Clara Shapiro-Koss
, Hong Zhang
, Annalisa DiRuscio
, Hanna S. Radomska
, Alexander K. Ebralidze
, Giovanni Amabile
, Min Ye
, Junyan Zhang
, Irene Lowers
, Roberto Avellino
, Ari Melnick
, Maria E. Figueroa
, Peter J.M. Valk
, Ruud Delwel
, Daniel G. Tenen

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

Abstract

C/EBPs are a family of transcription factors that regulate growth control and differentiation of various tissues. We found that C/EBPγ is highly upregulated in a subset of acute myeloid leukemia (AML) samples characterized by C/EBPα hypermethylation/silencing. Similarly, C/EBPγ was upregulated in murine hematopoietic stem/progenitor cells lacking C/EBPα, as C/EBPα mediates C/EBPγ suppression. Studies in myeloid cells demonstrated that CEBPG overexpression blocked neutrophilic differentiation. Further, downregulation of Cebpg in murine Cebpa-deficient stem/progenitor cells or in human CEBPA-silenced AML samples restored granulocytic differentiation. In addition, treatment of these leukemias with demethylating agents restored the C/EBPα-C/EBPγ balance and upregulated the expression of myeloid differentiation markers. Our results indicate that C/EBPγ mediates the myeloid differentiation arrest induced by C/EBPα deficiency and that targeting the C/EBPα-C/EBPγ axis rescues neutrophilic differentiation in this unique subset of AMLs.

Original language	English
Pages (from-to)	4490-4504
Number of pages	15
Journal	Journal of Clinical Investigation
Volume	122
Issue number	12
DOIs	https://doi.org/10.1172/JCI65102
Publication status	Published - 3 Dec 2012
Externally published	Yes

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Alberich-Jordà, M., Wouters, B., Balastik, M., Shapiro-Koss, C., Zhang, H., DiRuscio, A., Radomska, H. S., Ebralidze, A. K., Amabile, G., Ye, M., Zhang, J., Lowers, I., Avellino, R., Melnick, A., Figueroa, M. E., Valk, P. J. M., Delwel, R., & Tenen, D. G. (2012). C/EBPγ deregulation results in differentiation arrest in acute myeloid leukemia. Journal of Clinical Investigation, 122(12), 4490-4504. https://doi.org/10.1172/JCI65102

@article{fa7d05fdafc647bdbfaa4afe555d0f9f,

title = "C/EBPγ deregulation results in differentiation arrest in acute myeloid leukemia",

abstract = "C/EBPs are a family of transcription factors that regulate growth control and differentiation of various tissues. We found that C/EBPγ is highly upregulated in a subset of acute myeloid leukemia (AML) samples characterized by C/EBPα hypermethylation/silencing. Similarly, C/EBPγ was upregulated in murine hematopoietic stem/progenitor cells lacking C/EBPα, as C/EBPα mediates C/EBPγ suppression. Studies in myeloid cells demonstrated that CEBPG overexpression blocked neutrophilic differentiation. Further, downregulation of Cebpg in murine Cebpa-deficient stem/progenitor cells or in human CEBPA-silenced AML samples restored granulocytic differentiation. In addition, treatment of these leukemias with demethylating agents restored the C/EBPα-C/EBPγ balance and upregulated the expression of myeloid differentiation markers. Our results indicate that C/EBPγ mediates the myeloid differentiation arrest induced by C/EBPα deficiency and that targeting the C/EBPα-C/EBPγ axis rescues neutrophilic differentiation in this unique subset of AMLs.",

author = "Meritxell Alberich-Jord{\`a} and Bas Wouters and Martin Balastik and Clara Shapiro-Koss and Hong Zhang and Annalisa DiRuscio and Radomska, \{Hanna S.\} and Ebralidze, \{Alexander K.\} and Giovanni Amabile and Min Ye and Junyan Zhang and Irene Lowers and Roberto Avellino and Ari Melnick and Figueroa, \{Maria E.\} and Valk, \{Peter J.M.\} and Ruud Delwel and Tenen, \{Daniel G.\}",

year = "2012",

month = dec,

day = "3",

doi = "10.1172/JCI65102",

language = "English",

volume = "122",

pages = "4490--4504",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "American Society for Clinical Investigation",

number = "12",

}

Alberich-Jordà, M, Wouters, B, Balastik, M, Shapiro-Koss, C, Zhang, H, DiRuscio, A, Radomska, HS, Ebralidze, AK, Amabile, G, Ye, M, Zhang, J, Lowers, I, Avellino, R, Melnick, A, Figueroa, ME, Valk, PJM, Delwel, R & Tenen, DG 2012, 'C/EBPγ deregulation results in differentiation arrest in acute myeloid leukemia', Journal of Clinical Investigation, vol. 122, no. 12, pp. 4490-4504. https://doi.org/10.1172/JCI65102

TY - JOUR

T1 - C/EBPγ deregulation results in differentiation arrest in acute myeloid leukemia

AU - Alberich-Jordà, Meritxell

AU - Wouters, Bas

AU - Balastik, Martin

AU - Shapiro-Koss, Clara

AU - Zhang, Hong

AU - DiRuscio, Annalisa

AU - Radomska, Hanna S.

AU - Ebralidze, Alexander K.

AU - Amabile, Giovanni

AU - Ye, Min

AU - Zhang, Junyan

AU - Lowers, Irene

AU - Avellino, Roberto

AU - Melnick, Ari

AU - Figueroa, Maria E.

AU - Valk, Peter J.M.

AU - Delwel, Ruud

AU - Tenen, Daniel G.

PY - 2012/12/3

Y1 - 2012/12/3

N2 - C/EBPs are a family of transcription factors that regulate growth control and differentiation of various tissues. We found that C/EBPγ is highly upregulated in a subset of acute myeloid leukemia (AML) samples characterized by C/EBPα hypermethylation/silencing. Similarly, C/EBPγ was upregulated in murine hematopoietic stem/progenitor cells lacking C/EBPα, as C/EBPα mediates C/EBPγ suppression. Studies in myeloid cells demonstrated that CEBPG overexpression blocked neutrophilic differentiation. Further, downregulation of Cebpg in murine Cebpa-deficient stem/progenitor cells or in human CEBPA-silenced AML samples restored granulocytic differentiation. In addition, treatment of these leukemias with demethylating agents restored the C/EBPα-C/EBPγ balance and upregulated the expression of myeloid differentiation markers. Our results indicate that C/EBPγ mediates the myeloid differentiation arrest induced by C/EBPα deficiency and that targeting the C/EBPα-C/EBPγ axis rescues neutrophilic differentiation in this unique subset of AMLs.

AB - C/EBPs are a family of transcription factors that regulate growth control and differentiation of various tissues. We found that C/EBPγ is highly upregulated in a subset of acute myeloid leukemia (AML) samples characterized by C/EBPα hypermethylation/silencing. Similarly, C/EBPγ was upregulated in murine hematopoietic stem/progenitor cells lacking C/EBPα, as C/EBPα mediates C/EBPγ suppression. Studies in myeloid cells demonstrated that CEBPG overexpression blocked neutrophilic differentiation. Further, downregulation of Cebpg in murine Cebpa-deficient stem/progenitor cells or in human CEBPA-silenced AML samples restored granulocytic differentiation. In addition, treatment of these leukemias with demethylating agents restored the C/EBPα-C/EBPγ balance and upregulated the expression of myeloid differentiation markers. Our results indicate that C/EBPγ mediates the myeloid differentiation arrest induced by C/EBPα deficiency and that targeting the C/EBPα-C/EBPγ axis rescues neutrophilic differentiation in this unique subset of AMLs.

UR - https://www.scopus.com/pages/publications/84870504921

U2 - 10.1172/JCI65102

DO - 10.1172/JCI65102

M3 - Article

SN - 0021-9738

VL - 122

SP - 4490

EP - 4504

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 12

ER -

C/EBPγ deregulation results in differentiation arrest in acute myeloid leukemia

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