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

Human Genetics

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

39 Scopus citations

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 (US)
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
State	Published - Dec 3 2012

ASJC Scopus subject areas

Medicine(all)

Access to Document

10.1172/JCI65102

Fingerprint Dive into the research topics of 'C/EBPγ deregulation results in differentiation arrest in acute myeloid leukemia'. Together they form a unique fingerprint.

Cite this

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

C/EBPγ deregulation results in differentiation arrest in acute myeloid leukemia. / Alberich-Jordà, Meritxell; Wouters, Bas; Balastik, Martin; Shapiro-Koss, Clara; Zhang, Hong; DiRuscio, Annalisa; Radomska, Hanna S.; Ebralidze, Alexander K.; Amabile, Giovanni; Ye, Min; Zhang, Junyan; Lowers, Irene; Avellino, Roberto; Melnick, Ari; Figueroa, Maria E.; Valk, Peter J.M.; Delwel, Ruud; Tenen, Daniel G.

In: Journal of Clinical Investigation, Vol. 122, No. 12, 03.12.2012, p. 4490-4504.

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

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

Alberich-Jordà, Meritxell ; Wouters, Bas ; Balastik, Martin ; Shapiro-Koss, Clara ; Zhang, Hong ; DiRuscio, Annalisa ; Radomska, Hanna S. ; Ebralidze, Alexander K. ; Amabile, Giovanni ; Ye, Min ; Zhang, Junyan ; Lowers, Irene ; Avellino, Roberto ; Melnick, Ari ; Figueroa, Maria E. ; Valk, Peter J.M. ; Delwel, Ruud ; Tenen, Daniel G. / C/EBPγ deregulation results in differentiation arrest in acute myeloid leukemia. In: Journal of Clinical Investigation. 2012 ; Vol. 122, No. 12. pp. 4490-4504.

@article{e9966cf60457430ca74522ec903dc06c,

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 (US)",

volume = "122",

pages = "4490--4504",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "The American Society for Clinical Investigation",

number = "12",

}

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 - http://www.scopus.com/inward/record.url?scp=84870504921&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84870504921&partnerID=8YFLogxK

U2 - 10.1172/JCI65102

DO - 10.1172/JCI65102

M3 - Article

C2 - 23160200

AN - SCOPUS:84870504921

VL - 122

SP - 4490

EP - 4504

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 12

ER -