C/EBR gamma deregulation results in differentiation arrest in acute myeloid leukemia

M (Meritxell) Alberich Jorda; Bas Wouters; M Balastik; C Shapiro-Koss; H Zhang; A DiRuscio; HS Radomska; AK Ebralidze; G Amabile; M Ye; JY Zhang; I Lowers; Roberto Avellino; A Melnick; ME Figueroa; Peter Valk; Ruud Delwel; DG Tenen

doi:10.1172/JCI65102

C/EBR gamma deregulation results in differentiation arrest in acute myeloid leukemia

M (Meritxell) Alberich Jorda, Bas Wouters, M Balastik, C Shapiro-Koss, H Zhang, A DiRuscio, HS Radomska, AK Ebralidze, G Amabile, M Ye, JY Zhang, I Lowers, Roberto Avellino, A Melnick, ME Figueroa, Peter Valk, Ruud Delwel, DG Tenen

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

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Abstract

C/EBPs are a family of transcription factors that regulate growth. control and differentiation of various tissues. We found that C/EBP gamma is highly upregulated in a subset of acute Myeloid leukemia (AML) samples characterized by C/EBP alpha hypermethylation/silencing Similarly, C/EBP gamma was upregulated in murine hematopoietic stem/progenitor cells lacking C/EBP alpha, as C/EBP alpha mediates C/EBP gamma suppression. Studies in myeloid cells demonstrated that CEBP6 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 hi addition, treatment of these leukemias with demethylating agents restored the. C/EBP alpha-C/EBP gamma balance and upregulated the expression of myeloid differentiation markers. Our-results indicate that C/EBP gamma mediates the myeloid differentiation arrest induced by C/EBP alpha deficiency and that targeting the C/EBP alpha-C/EBP gamma 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 - 2013

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10.1172/JCI65102

http://hdl.handle.net/1765/60889

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Alberich Jorda, M., Wouters, B., Balastik, M., Shapiro-Koss, C., Zhang, H., DiRuscio, A., Radomska, HS., Ebralidze, AK., Amabile, G., Ye, M., Zhang, JY., Lowers, I., Avellino, R., Melnick, A., Figueroa, ME., Valk, P., Delwel, R., & Tenen, DG. (2013). C/EBR gamma deregulation results in differentiation arrest in acute myeloid leukemia. Journal of Clinical Investigation, 122(12), 4490-4504. https://doi.org/10.1172/JCI65102

@article{3094789095c84f9881faa9bfd5420504,

title = "C/EBR gamma 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/EBP gamma is highly upregulated in a subset of acute Myeloid leukemia (AML) samples characterized by C/EBP alpha hypermethylation/silencing Similarly, C/EBP gamma was upregulated in murine hematopoietic stem/progenitor cells lacking C/EBP alpha, as C/EBP alpha mediates C/EBP gamma suppression. Studies in myeloid cells demonstrated that CEBP6 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 hi addition, treatment of these leukemias with demethylating agents restored the. C/EBP alpha-C/EBP gamma balance and upregulated the expression of myeloid differentiation markers. Our-results indicate that C/EBP gamma mediates the myeloid differentiation arrest induced by C/EBP alpha deficiency and that targeting the C/EBP alpha-C/EBP gamma axis rescues neutrophilic differentiation in this unique subset of AMLs.",

author = "{Alberich Jorda}, {M (Meritxell)} and Bas Wouters and M Balastik and C Shapiro-Koss and H Zhang and A DiRuscio and HS Radomska and AK Ebralidze and G Amabile and M Ye and JY Zhang and I Lowers and Roberto Avellino and A Melnick and ME Figueroa and Peter Valk and Ruud Delwel and DG Tenen",

year = "2013",

doi = "10.1172/JCI65102",

language = "English",

volume = "122",

pages = "4490--4504",

journal = "Journal of Clinical Investigation",

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publisher = "The American Society for Clinical Investigation",

number = "12",

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Alberich Jorda, M, Wouters, B, Balastik, M, Shapiro-Koss, C, Zhang, H, DiRuscio, A, Radomska, HS, Ebralidze, AK, Amabile, G, Ye, M, Zhang, JY, Lowers, I, Avellino, R, Melnick, A, Figueroa, ME, Valk, P , Delwel, R & Tenen, DG 2013, 'C/EBR gamma 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/EBR gamma deregulation results in differentiation arrest in acute myeloid leukemia

AU - Alberich Jorda, M (Meritxell)

AU - Wouters, Bas

AU - Balastik, M

AU - Shapiro-Koss, C

AU - Zhang, H

AU - DiRuscio, A

AU - Radomska, HS

AU - Ebralidze, AK

AU - Amabile, G

AU - Ye, M

AU - Zhang, JY

AU - Lowers, I

AU - Avellino, Roberto

AU - Melnick, A

AU - Figueroa, ME

AU - Valk, Peter

AU - Delwel, Ruud

AU - Tenen, DG

PY - 2013

Y1 - 2013

N2 - C/EBPs are a family of transcription factors that regulate growth. control and differentiation of various tissues. We found that C/EBP gamma is highly upregulated in a subset of acute Myeloid leukemia (AML) samples characterized by C/EBP alpha hypermethylation/silencing Similarly, C/EBP gamma was upregulated in murine hematopoietic stem/progenitor cells lacking C/EBP alpha, as C/EBP alpha mediates C/EBP gamma suppression. Studies in myeloid cells demonstrated that CEBP6 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 hi addition, treatment of these leukemias with demethylating agents restored the. C/EBP alpha-C/EBP gamma balance and upregulated the expression of myeloid differentiation markers. Our-results indicate that C/EBP gamma mediates the myeloid differentiation arrest induced by C/EBP alpha deficiency and that targeting the C/EBP alpha-C/EBP gamma 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/EBP gamma is highly upregulated in a subset of acute Myeloid leukemia (AML) samples characterized by C/EBP alpha hypermethylation/silencing Similarly, C/EBP gamma was upregulated in murine hematopoietic stem/progenitor cells lacking C/EBP alpha, as C/EBP alpha mediates C/EBP gamma suppression. Studies in myeloid cells demonstrated that CEBP6 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 hi addition, treatment of these leukemias with demethylating agents restored the. C/EBP alpha-C/EBP gamma balance and upregulated the expression of myeloid differentiation markers. Our-results indicate that C/EBP gamma mediates the myeloid differentiation arrest induced by C/EBP alpha deficiency and that targeting the C/EBP alpha-C/EBP gamma axis rescues neutrophilic differentiation in this unique subset of AMLs.

U2 - 10.1172/JCI65102

DO - 10.1172/JCI65102

M3 - Article

VL - 122

SP - 4490

EP - 4504

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 12

ER -

C/EBR gamma deregulation results in differentiation arrest in acute myeloid leukemia

Abstract

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