Modeling of C/EBPα Mutant Acute Myeloid Leukemia Reveals a Common Expression Signature of Committed Myeloid Leukemia-Initiating Cells

Kirstetter, Peggy; Schuster, Mikkel Bruhn; Bereshchenko, Oxana; Moore, Susan; Dvinge, Heidi; Kurz, Elke; Theilgaard‐Mönch, Kim; Månsson, Robert; Pedersen, Thomas Åskov; Pabst, Thomas; Schröck, Evelin; Porse, Bo T.; Jacobsen, Sten Eirik W.; Bertone, Paul; Tenen, Daniel G.; Nerlov, Claus

doi:10.1016/j.ccr.2008.02.008

Cited by 231 publications

(272 citation statements)

References 38 publications

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“…17,20 However, previous studies did not find leukemic potential in mice carrying monoallelic Cebpa L/ þ or Cebpa K/ þ mutations. 11,18 On the other hand, it has been shown that FLT3 ITD can phosphorylate C/EBPa, which could lead to a loss of function in the absence of other mutations explaining why some AML only carry a monoallelic C/EBPa mutation. 21,22 In addition, recent work using retroviral overexpression demonstrated that a C-terminal Cebpa mutation (C/EBPa-C m ) was sufficient to cause AML and that FLT3 ITD could shorten the latency of AML induced by C/EBPa-C m .…”

Section: Resultsmentioning

confidence: 99%

“…11,14,18 Briefly, insertion of a premature stop codon between the p42 and p30 C/EBPa start sites results in exclusive p30 C/EBPa translation (Cebpa Lp30 or L allele; Cebpa L/ þ ). The K313KK mutation was generated by insertion of an additional lysine in the C/EBPa coding sequence (Cebpa K313KK or K allele; Cebpa K/ þ ) leading to disruption of the basic region leucine zipper of C/EBPa.…”

Section: Mouse Strainsmentioning

confidence: 99%

“…One strain contains an ITD mutation in the endogenous murine Flt3 locus, 14 which was cross-bred with a knockin of an N-terminal Cebpa mutation (Lp30 or L allele) 18 and a C-terminal Cebpa mutation (K313 duplication: K313KK or K allele). 11 This model for human AML enabled us to appropriately study the molecular and cellular background of leukemia initiation and maintenance.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Resultsmentioning

confidence: 99%

Section: Mouse Strainsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2012

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“…The combination of N-and C-terminal mutations have distinct features that result in leukaemia development (23,24). Murine knockin studies investigating p30 oncogenicity in the absence of C/EBPα p42 showed that p30 induced fully penetrant transplantable AML (25). p30 is sufficient for haematopoietic commitment to the myeloid lineage, it enables transition from the common myeloid progenitor (CMP) to the GMP stage.…”

Section: Introductionmentioning

confidence: 99%

“…p30 is sufficient for haematopoietic commitment to the myeloid lineage, it enables transition from the common myeloid progenitor (CMP) to the GMP stage. However it does not retain the ability to control proliferation and myeloid progenitors have greatly increased self renewal capacities (25).…”

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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Transcriptional and translational control of C/EBPs: The case for “deep” genetics to understand physiological function

Nerlov

2010

BioEssays

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The complexity of organisms is not simply determined by the number of their genes, but to a large extent by how gene expression is controlled. In addition to transcriptional regulation, this involves several layers of post-transcriptional control, such as translational repression, microRNA-mediated mRNA degradation and translational inhibition, alternative splicing, and the regulated generation of functionally distinct gene products from a single mRNA through alternative use of translation initiation sites. Much progress has been made in describing the molecular basis for these gene regulatory mechanisms. However, it is now a major challenge to translate this knowledge into deeper understanding of the physiological processes, both normal and pathological, that they govern. Using the C/EBP family of transcription factors as an example, the present review describes recent genetic experiments addressing this general problem and discusses how the physiological importance of newly discovered regulatory mechanisms might be determined.

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Modeling of C/EBPα Mutant Acute Myeloid Leukemia Reveals a Common Expression Signature of Committed Myeloid Leukemia-Initiating Cells

Cited by 231 publications

References 38 publications

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

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

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

Transcriptional and translational control of C/EBPs: The case for “deep” genetics to understand physiological function

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