Block of C/EBPα function by phosphorylation in acute myeloid leukemia with FLT3 activating mutations

Radomska, Hanna S.; Bassères, Daniela S.; Zheng, Rui; Zhang, Pu; Dayaram, Tajhal; Yamamoto, Yukiya; Sternberg, David; Lokker, Nathalie A.; Giese, Neill A.; Bohlander, Stefan K.; Schnittger, Susanne; Delmotte, Marie Hélène; Davis, Roger J.; Small, Donald; Hiddemann, Wolfgang; Gilliland, D. Gary; Tenen, Daniel G.

doi:10.1084/jem.20052242

Cited by 177 publications

(194 citation statements)

References 65 publications

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“…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 . 23 To elucidate this discrepancy, we also monitored hematopoietic chimeras with single, either N-terminal (L allele) or C-terminal…”

Section: Resultsmentioning

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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Section: Resultsmentioning

confidence: 99%

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

et al. 2012

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“…108 Recent reports have demonstrated that MEK/MAPK inhibition can release cells from FLT3-ITD-mediated differentiation blockade. 109 These findings suggest that MEK is a rational target for combination studies with available FLT3 inhibitors.…”

Section: Flt3 Monoclonal Anitbodiesmentioning

confidence: 98%

Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia

2012

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Acute myeloid leukemia (AML) is a highly heterogenous disease with multiple signaling pathways contributing to its pathogenesis. A key driver of AML is the FMS-like tyrosine kinase receptor-3 (FLT3). Activating mutations in FLT3, primarily the FLT3-internal tandem duplication (FLT3-ITD), are associated with decreased progression-free and overall survival. Identification of the importance of FLT3-ITD and the FLT3 pathway in the prognosis of patients with AML has stimulated efforts to develop therapeutic inhibitors of FLT3. Although these inhibitors have shown promising antileukemic activity, they have had limited efficacy to date as single agents and may require use in combination with cytotoxic chemotherapies. Here, we review clinical and preclinical results for the clinically mature FLT3 inhibitors currently in development. We conclude that multitargeted FLT3 inhibitors may have more utility earlier in the course of disease, when in vitro evidence suggests that AML cells are less dependent on FLT3 signaling, perhaps because of upregulation of multiple other signaling pathways. More potent agents may have greater utility in relapsed and heavily pretreated patients, in whom high levels of circulating FLT3 ligand may necessitate use of an agent with a very favorable pharmacokinetic/ pharmacodynamic profile. Novel combination regimens are also discussed.

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“…Leukemias involving the internal tandem duplication (ITD) in FLT-3 (Fms-like tyrosine kinase 3) that constitutively activates FLT-3 kinase activity have been reported to block C/EBPα function via phosphorylation at Serine 21 (S21) in the C/EBPα protein. Hence, the increased FLT-3 activity appears to both increase cellular proliferation and increase cell viability and also prevent C/EBPα from inducing granulocytic differentiation [18]. Decreased expression of C/EBPα has also been described in AML with the t(8;21) translocation resulting in the AML1-ETO fusion protein.…”

Section: Ccaat Enhancer Binding Protein Alpha (C/ebpα)mentioning

confidence: 98%

“…In leukemias harboring the FLT-3-ITD mutation, constitutive FLT-3 kinase activity results in sustained phosphorylation at S21 in the C/EBPα protein. Phosphorylation at S21 in turn has been shown to interfere with the ability of C/EBPα to induce granulocytic differentiation, an observation that may explain the differentiation block associated with leukemia [18].…”

Section: Ccaat Enhancer Binding Protein Alpha (C/ebpα)mentioning

confidence: 99%

Sumoylation and the function of CCAAT enhancer binding protein alpha (C/EBPα)

Khanna-Gupta

2008

Blood Cells, Molecules, and Diseases

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CCAAT enhancer binding protein alpha (C/EBPα) is the founding member of a family of basic region/leucine zipper (bzip) transcription factors and is a master regulator of granulopoiesis. It is expressed at high levels throughout myeloid differentiation and binds to the promoters of multiple myeloid-specific genes at different stages of myeloid maturation. Profound hematopoietic abnormalities occur in mice nullizygous for C/EBPα̤ including a selective early block in the differentiation of granulocytes. Mutations in C/EBPα are present in a subset of patients with AML presenting with a normal karyotype. These mutations can result in the expression of a 30kD dominant negative C/EBPα isoform, which contributes to loss of C/EBPα function. The molecular basis for this observation remains unknown. In addition to phoshorylation, C/EBPα is modified, posttranslationally by a small ubiquitin-related modifier (SUMO) at a lysine residue (K159), which lies within the growth inhibitory region of the C/EBPα protein. Sumoylation at K159 in the C/EBPα protein prevents association of the SWI/SNF chromatin remodeling complex with C/EBPα, thereby hampering transactivation. In this review, the functional implications of post-translational modification, particularly sumoylation, of C/EBPα in normal granulopoiesis and leukemia are considered.

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Block of C/EBPα function by phosphorylation in acute myeloid leukemia with FLT3 activating mutations

Cited by 177 publications

References 65 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

Targeting the FMS-like tyrosine kinase 3 in acute myeloid leukemia

Sumoylation and the function of CCAAT enhancer binding protein alpha (C/EBPα)

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