Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity

Taskesen, Erdogan; Bullinger, Lars; Corbacioglu, Andrea; Sanders, Mathijs A.; Erpelinck, Claudia; Wouters, Bas J.; Luytgaarde, Sonja C. van der Poel-van de; Damm, Frédérik; Krauter, Jürgen; Ganser, Arnold; Schlenk, Richard F.; Löwenberg, Bob; Delwel, Ruud; Döhner, Hartmut; Valk, Peter J.M.; Döhner, Konstanze

doi:10.1182/blood-2010-09-307280

Cited by 344 publications

(316 citation statements)

References 40 publications

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“…In AML, oncogene-mediated dysregulation of C/EBPα mRNA expression and/or protein activity occurs in CEBPA is an intronless gene with N-terminal transcriptional activation domains and a C-terminal basic region leucine zipper (LZ) domain. CEBPA mutations, which occur across the entire coding region, are present in 5% and 10% of childhood and adult AML respectively (6). Somatic and inherited mutations in CEBPA co-occur, are often bi-allelic, and are found with higher frequency in cytogenetically normal (CN) AML (7,8).…”

Section: Introductionmentioning

confidence: 99%

The presence of C/EBPα and its degradation are both required for TRIB2-mediated leukaemia

et al. 2016

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C/EBPα (p42 and p30 isoforms) is commonly dysregulated in cancer via the action of oncogenes, and specifically in acute myeloid leukaemia (AML) by mutation. Elevated TRIB2 leads to the degradation of C/EBPα p42, leaving p30 intact in AML. Whether this relationship is a cooperative event in AML transformation is not known and the molecular mechanism involved remains elusive.Using mouse genetics our data reveal that in the complete absence of C/EBPα TRIB2 was unable to induce AML. Only in the presence of C/EBPα p42 and p30 were TRIB2 and p30 able to cooperate to decrease the latency of disease. We demonstrate the molecular mechanism involved in degradation of C/EBPα p42 requires site-specific direct interaction between TRIB2 and C/EBPα p42 for the K48-specific ubiquitin-dependent proteasomal degradation of C/EBPα p42. This interaction and ubiquitination is dependent on a critical C-terminal lysine residue on C/EBPα. We show effective targeting of this pathway pharmacologically using proteasome inhibitors in TRIB2 positive AML cells. Together, our data show that excess p30 cooperated with TRIB2 only in the presence of p42 to accelerate AML and the direct interaction and degradation of C/EBPα p42 is required for TRIB2-mediated AML.

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Section: Introductionmentioning

confidence: 99%

The presence of C/EBPα and its degradation are both required for TRIB2-mediated leukaemia

et al. 2016

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“…14,15 Clinical data demonstrate CEBPA mutations as a reoccurring partner in AML with FLT3 ITD. 5,16,17 However, there is no study investigating FLT3 ITD in cooperation with CEBPA mutations where FLT3 ITD or both oncogenes are expressed from their own promoter at the original locus.…”

Section: Introductionmentioning

confidence: 99%

Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model

et al. 2012

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Biallelic CEBPA mutations and FMS-like tyrosine kinase receptor 3 (FLT3) length mutations are frequently identified in human acute myeloid leukemia (AML) with normal cytogenetics. However, the molecular and cellular mechanisms of oncogene cooperation remain unclear because of a lack of disease models. We have generated an AML mouse model using knockin mouse strains to study cooperation of an internal tandem duplication (ITD) mutation in the Flt3 gene with commonly observed CCAAT/enhancer binding protein alpha (C/EBPa) mutations. This study provides evidence that FLT3 ITD cooperates in leukemogenesis by enhancing the generation of leukemia-initiating granulocyte-monocyte progenitors (GMPs) otherwise prevented by a block in differentiation and skewed lineage priming induced by biallelic C/EBPa mutations. These cellular changes are accompanied by an upregulation of hematopoietic stem cell and STAT5 target genes. By gene expression analysis in premalignant populations, we further show a role of FLT3 ITD in activating genes involved in survival/transformation and chemoresistance. Both multipotent progenitors and GMP cells contain the potential to induce AML similar to corresponding cells in human AML samples showing that this model resembles human disease.

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“…Many ITP patients, particularly patients with anti-GP Ib-IX autoantibodies, do not respond to conventional treatments such as steroids, intravenous immunoglobulins, or splenectomy [4][5][6][7][8]. Also the role of new therapies like thrombopoietin agonist are unclear and not without risks [9].…”

Section: Sialidase Inhibition To Increase Platelet Counts: a New Treamentioning

confidence: 99%

“…CEBPA mutations are found in ;10% of AML [1] with two main hotspots i.e., N-terminal out-of-frame mutations abolish translation of the full-length isoform and C-terminal mutations of the basic leucine zipper domain disrupting DNA binding or dimerization [2]. The majority of mutations are bi-allelic or double, however, homozygous mutations have been described [3,4].…”

mentioning

confidence: 99%

Classification of CEBPA mutated acute myeloid leukemia by GATA2 mutations

et al. 2015

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Prognostic impact, concurrent genetic mutations, and gene expression features of AML with CEBPA mutations in a cohort of 1182 cytogenetically normal AML patients: further evidence for CEBPA double mutant AML as a distinctive disease entity

Cited by 344 publications

References 40 publications

The presence of C/EBPα and its degradation are both required for TRIB2-mediated leukaemia

The presence of C/EBPα and its degradation are both required for TRIB2-mediated leukaemia

Molecular and cellular effects of oncogene cooperation in a genetically accurate AML mouse model

Classification of CEBPA mutated acute myeloid leukemia by GATA2 mutations

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