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

被引：53

作者：

Alberich-Jorda, Meritxell ^{[2
]}

Wouters, Bas ^{[3
]}

Balastik, Martin ^{[2
,4
]}

Shapiro-Koss, Clara ^{[3
]}

Zhang, Hong ^{[2
]}

DiRuscio, Annalisa ^{[2
]}

Radomska, Hanna S. ^{[2
]}

Ebralidze, Alexander K. ^{[2
]}

Amabile, Giovanni ^{[2
]}

Ye, Min ^{[2
]}

Zhang, Junyan ^{[2
]}

Lowers, Irene ^{[3
]}

Avellino, Roberto ^{[3
]}

Melnick, Ari ^{[5
]}

Figueroa, Maria E. ^{[6
]}

Valk, Peter J. M. ^{[3
]}

Delwel, Ruud ^{[3
]}

Tenen, Daniel G. ^{[1
,2
,7
]}

机构：

[1] Harvard Univ, Harvard Stem Cell Inst, Sch Med, Ctr Life Sci, Boston, MA 02115 USA

[2] Beth Israel Deaconess Med Ctr, Boston, MA 02215 USA

[3] Erasmus Univ, Med Ctr, Rotterdam, Netherlands

[4] ASCR, Inst Mol Genet, Prague, Czech Republic

[5] Weill Cornell Med Coll, New York, NY USA

[6] Univ Michigan, Ann Arbor, MI 48109 USA

[7] Natl Univ Singapore, Canc Sci Inst, Singapore 117548, Singapore

来源：

JOURNAL OF CLINICAL INVESTIGATION | 2012年 / 122卷 / 12期

关键词：

COLONY-STIMULATING-FACTOR; ENHANCER-BINDING-PROTEIN; ACUTE PROMYELOCYTIC LEUKEMIA; GENE-EXPRESSION PROFILES; TRANSCRIPTION FACTOR; CEBPA MUTATIONS; RETINOIC ACID; GRANULE DEFICIENCY; MOLECULAR-CLONING; TUMOR-SUPPRESSOR;

D O I：

10.1172/JCI65102

中图分类号：

R-3 [医学研究方法]; R3 [基础医学];

学科分类号：

1001 ;

摘要：

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.

引用

页码：4490 / 4504

页数：15

共 80 条

[1] The C/EBPδ tumor suppressor is silenced by hypermethylation in acute myeloid leukemia [J].

Agrawal, Shuchi ;

Hofmann, Wolf-Karsten ;

Tidow, Nicola ;

Ehrich, Mathias ;

van den Boom, Dirk ;

Koschmieder, Steffen ;

Berdel, Wolfgang E. ;

Serve, Hubert ;

Mueller-Tidow, Carsten .

BLOOD, 2007, 109 (09) :3895-3905

[2]

[Anonymous], 2006, EUR J INT L

[3]

[Anonymous], BLOOD

[4] The in vivo profile of transcription factors during neutrophil differentiation in human bone marrow [J].

Bjerregaard, MD ;

Jurlander, J ;

Klausen, P ;

Borregaard, N ;

Cowland, JB .

BLOOD, 2003, 101 (11) :4322-4332

[5] BiQ analyzer: visualization and quality control for DNA methylation data from bisulfite sequencing [J].

Bock, C ;

Reither, S ;

Mikeska, T ;

Paulsen, M ;

Walter, J ;

Lengauer, T .

BIOINFORMATICS, 2005, 21 (21) :4067-4068

[6] A PMLRAR alpha transgene initiates murine acute promyelocytic leukemia [J].

Brown, D ;

Kogan, S ;

Lagasse, E ;

Weissman, I ;

Alcalay, M ;

Pelicci, PG ;

Atwater, S ;

Bishop, JM .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1997, 94 (06) :2551-2556

[7] ACUTE PROMYELOCYTIC LEUKEMIA - FROM CLINIC TO MOLECULAR-BIOLOGY [J].

CHEN, SJ ;

WANG, ZY ;

CHEN, Z .

STEM CELLS, 1995, 13 (01) :22-31

[8]

CHEN Z, 1994, CR ACAD SCI III-VIE, V317, P1135

[9] Infrequent hypermethylation of CEBPA promotor in acute myeloid leukaemia [J].

Chim, CS ;

Wong, ASY ;

Kwong, YL .

BRITISH JOURNAL OF HAEMATOLOGY, 2002, 119 (04) :988-990

[10] Down-modulation of the C/EBPα transcription factor in core binding factor acute myeloid leukemias [J].

Cilloni, D ;

Carturan, S ;

Gottardi, E ;

Messa, F ;

Messa, E ;

Fava, M ;

Diverio, D ;

Guerrasio, A ;

Lo-Coco, F ;

Saglio, G .

BLOOD, 2003, 102 (07) :2705-2706

← 1 2 3 4 5 6 7 8 →