Epigenetic regulation of acute myeloid leukemia - Andreas Lennartsson
Acute myeloid leukemia (AML) has a poor prognosis in both, adults and children, with a long-term survival of only 15% and 50% respectively.
The mainstay of treatment, standard combination chemotherapy, appears to have reached the limit of its impact. There is therefore an urgent need for new novel therapeutics in childhood and adult acute leukemia’s. Improvements have been dramatic when the biology is well characterized, such as in the acute promyelocytic leukemia (APML) subtype, with cure rates now exceeding 90% for this subtype. These data demonstrate that a better understanding of AML biology is a pre-requisite for the development of novel therapies to improve treatment outcomes.
We and others have demonstrated that the generation of tissue-specific patterns of gene expression involves the interplay of combinatorial patterns of specific enhancer elements with their cognate promoters. We predict that the normal epigenetic remodeling of enhancers, which are required to generate specialized transcriptional programs that are necessary for hematopoietic development, is corrupted during the evolution of leukemia. Although we know that transcription is altered and drives the leukemic phenotype in the majority of AML cases, the mechanisms that initiate and maintain these aberrant transcriptional programs are poorly understood. Details of transcriptional alterations, the mechanisms involved and how these might be therapeutically targeted, will help us to identify novel therapeutic targets and therapies.
The relapse and consequently the poor prognosis of AML patients are often caused by leukemic stem cells. AML is associated with perturbed epigenetic regulation, with both mutations in and chromosomal rearrangements of epigenetic factors. Therefore, the aim of this project is to investigate the regulatory epigenetic molecular mechanisms of leukemic stem cells.
Our specific aims are to:
- Map how the epigenetic modifications that are connected to enhancers are disturbed in acute myeloid leukemic stem cells.
- Characterize the effect the deregulated epigenetic modifications have on enhancer activity and on the transcriptional program that creates and stabilize multi-potency.
- Identify key epigenetic factors that regulate enhancer activity and multi-potency in hematopoietic stem cells.
- Investigate whether these epigenetic factors are deregulated in AML and how they contribute to the leukemic phenotype.
- Analyze the role of the identified epigenetic factors have in drug resistance.
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Differential methylation in CN-AML preferentially targets non-CGI regions and is dictated by DNMT3A mutational status and associated with predominant hypomethylation of HOX genes.
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Leukemia associated mutant Wilms' tumor gene 1 protein promotes expansion of human hematopoietic progenitor cells.
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Antidepressant treatment is associated with epigenetic alterations in the promoter of P11 in a genetic model of depression.
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Prognostic DNA methylation patterns in cytogenetically normal acute myeloid leukemia are predefined by stem cell chromatin marks.
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Wilms' tumor gene 1 protein represses the expression of the tumor suppressor interferon regulatory factor 8 in human hematopoietic progenitors and in leukemic cells.
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Epigenetic aberrations in acute myeloid leukemia: Early key events during leukemogenesis.
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The roles of SNF2/SWI2 nucleosome remodeling enzymes in blood cell differentiation and leukemia.
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Histone modification patterns and epigenetic codes.
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Epigenetic alterations related to early life stressful events
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