CEBPA point mutations in hematological malignancies

The CCAAT/enhancer-binding protein-alpha (CEBPA) is a transcription factor strongly implicated in myelopoiesis through control of proliferation and differentiation of myeloid progenitors. Recently, several works have reported the presence of CEBPA-acquired mutations in hematological malignancies. In this work, we analyzed characteristics of mutations and their correlation with disease characteristics described in previous studies. In the 1175 patients reported, 146 CEBPA mutations were identified in 96 patients. Mutations were found in the whole gene sequence, but cluster regions were clearly identified. Furthermore, two categories of mutations were reported: out-of-frame ins/del often in the N-terminal region, and in-frame ins/del often in the C-terminal region. CEBPA mutations were reported exclusively in acute myeloid leukemia (AML) (according to WHO classification criteria) and mutated patients preferentially belonged to M1, M2 and M4 FAB subtypes. All but one case belonged to the ‘intermediate’ prognostic subgroup of MRC classification. In the absence of poor prognostic factors, patients with CEBPA mutation had favorable outcome, very similar to that of the t(8;21), inv(16), t(15;17) subgroup. Systematic analysis of CEBPA mutations, in addition to that of alterations in master genes of hematopoiesis, may be useful to assess the prognosis of AML particularly in patients belonging to the ‘intermediate’ prognostic subgroup.

[1]  G. Behre,et al.  Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-alpha (C/EBPalpha), in acute myeloid leukemia. , 2001, Nature genetics.

[2]  R. Verhaak,et al.  Prognostically useful gene-expression profiles in acute myeloid leukemia. , 2004, The New England journal of medicine.

[3]  S. Fröhling,et al.  CEBPA mutations in younger adults with acute myeloid leukemia and normal cytogenetics: prognostic relevance and analysis of cooperating mutations. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  J. R. Smith,et al.  CCAAT/enhancer-binding protein alpha (C/EBP alpha) inhibits cell proliferation through the p21 (WAF-1/CIP-1/SDI-1) protein. , 1996, Genes & development.

[5]  T. Kummalue,et al.  Cell cycle inhibition mediated by the outer surface of the C/EBPα basic region is required but not sufficient for granulopoiesis , 2003, Oncogene.

[6]  K Wheatley,et al.  The importance of diagnostic cytogenetics on outcome in AML: analysis of 1,612 patients entered into the MRC AML 10 trial. The Medical Research Council Adult and Children's Leukaemia Working Parties. , 1998, Blood.

[7]  Pu Zhang,et al.  Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-α (C/EBPα), in acute myeloid leukemia , 2001, Nature Genetics.

[8]  C. Calkhoven,et al.  Translation start site multiplicity of the CCAAT/enhancer binding protein alpha mRNA is dictated by a small 5' open reading frame. , 1994, Nucleic acids research.

[9]  U. Schibler,et al.  CCAAT/enhancer-binding protein mRNA is translated into multiple proteins with different transcription activation potentials. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[10]  C. Nerlov C/EBPα mutations in acute myeloid leukaemias , 2004, Nature Reviews Cancer.

[11]  C. Sorg,et al.  The transcription factors c-myb and C/EBP alpha regulate the monocytic/myeloic gene MRP14. , 1998, Immunobiology.

[12]  J. Licht,et al.  Transcription factors, normal myeloid development, and leukemia. , 1997, Blood.

[13]  C. Sorg,et al.  The Transcription Factors c-myb and C/EBPα Regulate the Monocytic/Myeloic Gene MRP14 , 1998 .

[14]  D. Tenen,et al.  Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein alpha-deficient mice. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[15]  D. Tenen,et al.  Granulocyte inducer C/EBPalpha inactivates the myeloid master regulator PU.1: possible role in lineage commitment decisions. , 2002, Blood.

[16]  Daniel G. Tenen,et al.  Disruption of differentiation in human cancer: AML shows the way , 2003, Nature Reviews Cancer.

[17]  C. Preudhomme,et al.  New mechanisms of AML1 gene alteration in hematological malignancies , 2003, Leukemia.

[18]  T. Golub,et al.  c-Myc Is a Critical Target for C/EBPα in Granulopoiesis , 2001, Molecular and Cellular Biology.

[19]  Y. Kwong,et al.  Infrequent hypermethylation of CEBPA promotor in acute myeloid leukaemia , 2002, British journal of haematology.

[20]  A. Friedman Transcriptional regulation of granulocyte and monocyte development , 2002, Oncogene.

[21]  M. Caligiuri,et al.  BCR-ABL suppresses C/EBPα expression through inhibitory action of hnRNP E2 , 2002, Nature Genetics.

[22]  J. Cayuela,et al.  Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA). , 2002, Blood.

[23]  D. Tenen,et al.  A dominant-negative mutant of C/EBPalpha, associated with acute myeloid leukemias, inhibits differentiation of myeloid and erythroid progenitors of man but not mouse. , 2004, Blood.

[24]  A. Friedman,et al.  C/EBPαp30, a myeloid leukemia oncoprotein, limits G-CSF receptor expression but not terminal granulopoiesis via site-selective inhibition of C/EBP DNA binding , 2004, Oncogene.

[25]  Torsten Haferlach,et al.  AML1–ETO downregulates the granulocytic differentiation factor C/EBPα in t(8;21) myeloid leukemia , 2001, Nature Medicine.

[26]  A. Friedman,et al.  CCAAT/enhancer-binding proteins are required for granulopoiesis independent of their induction of the granulocyte colony-stimulating factor receptor. , 2002, Blood.

[27]  D. Tenen,et al.  Reciprocal Roles for CCAAT/Enhancer Binding Protein (C/EBP) and PU.1 Transcription Factors in Langerhans Cell Commitment , 2002, The Journal of experimental medicine.

[28]  B. Calabretta,et al.  Transcription activation function of C/EBPalpha is required for induction of granulocytic differentiation. , 2003, Blood.

[29]  O. MacDougald,et al.  A 30-kDa alternative translation product of the CCAAT/enhancer binding protein alpha message: transcriptional activator lacking antimitotic activity. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[30]  D. Tenen,et al.  The amino terminal and E2F interaction domains are critical for C/EBP alpha-mediated induction of granulopoietic development of hematopoietic cells. , 2003, Blood.

[31]  Bob Löwenberg,et al.  Biallelic mutations in the CEBPA gene and low CEBPA expression levels as prognostic markers in intermediate-risk AML. , 2003, The hematology journal : the official journal of the European Haematology Association.

[32]  D. Tenen,et al.  CCAAT/Enhancer binding proteins repress the leukemic phenotype of acute myeloid leukemia. , 2003, Blood.

[33]  Huaitian Liu,et al.  Regulation of granulocyte and monocyte differentiation by CCAAT/enhancer binding protein alpha. , 2003, Blood cells, molecules & diseases.

[34]  F. Lo‐Coco,et al.  Down-modulation of the C/EBPalpha transcription factor in core binding factor acute myeloid leukemias. , 2003, Blood.

[35]  T. Lister,et al.  Mutations of CEBPA in acute myeloid leukemia FAB types M1 and M2 , 2003, Genes, chromosomes & cancer.

[36]  H. Gralnick,et al.  Proposals for the Classification of the Acute Leukaemias French‐American‐British (FAB) Co‐operative Group , 1976, British journal of haematology.

[37]  M. Caligiuri,et al.  BCR-ABL suppresses C/EBPalpha expression through inhibitory action of hnRNP E2. , 2002, Nature genetics.

[38]  A. Ganser,et al.  The emergence of a C/EBPα mutation in the clonal evolution of MDS towards secondary AML , 2003, Leukemia.

[39]  D. Tenen,et al.  PU.1 (Spi-1) and C/EBP alpha regulate the granulocyte colony-stimulating factor receptor promoter in myeloid cells. , 1996, Blood.

[40]  K. Akashi,et al.  Induction of granulocytic differentiation by 2 pathways. , 2002, Blood.

[41]  Carl W. Miller,et al.  Mutations in the gene encoding the transcription factor CCAAT/enhancer binding protein alpha in myelodysplastic syndromes and acute myeloid leukemias. , 2002, Blood.

[42]  D. Tenen,et al.  CCAAT/Enhancer Binding Protein α Is a Regulatory Switch Sufficient for Induction of Granulocytic Development from Bipotential Myeloid Progenitors , 1998, Molecular and Cellular Biology.

[43]  C. Nerlov C/EBPalpha mutations in acute myeloid leukaemias. , 2004, Nature reviews. Cancer.