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

43 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
Externally published	Yes

ASJC Scopus subject areas

Medicine(all)

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10.1172/JCI65102

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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

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.

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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.",

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AU - Alberich-Jordà, Meritxell

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AU - Balastik, Martin

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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.

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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.

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

Abstract

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