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 | |
| State | Published - Dec 3 2012 |
| Externally published | Yes |
Fingerprint
ASJC Scopus subject areas
- Medicine(all)
Cite this
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; 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
}
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
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 -