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Epigenetic Mechanisms in Acute Myeloid Leukemia

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Epigenetics and Disease

Part of the book series: Progress in Drug Research ((PDR,volume 67))

Abstract

Acute leukemia is characterized by clonal expansion of hematopoietic stem and progenitor cells with blocked differentiation. Clinical and experimental evidences suggest that acute myeloid leukemia (AML) is the product of several functionally cooperating genetic alterations including chromosomal translocations leading to expression of leukemogenic fusion proteins. Several AML-associated lesions target chromatin regulators like histone methyltransferases or histone acetyltransferases, including mixed-lineage leukemia 1 (MLL1) or CREB bindung protein/p300. Molecular and biochemical studies start to provide useful insights into the mechanisms of targeting and mode-of-action of such leukemogenic fusion proteins resulting in aberrant gene expression programs and AML. Chromatin modulating mechanisms are also mediating the transforming activity of key drivers of leukemogenesis by aberrant recruitment of corepressors. Recent large-scale screening efforts demonstrated that both aberrant DNA promoter methylation and aberrantly expressed microRNAs play an important role in the pathogenesis of AML as well. Current efforts to therapeutically exploit the potential reversibility of epigenetic mechanisms are focused on small molecules that inhibit DNA methyltransferases or histone deacetylases. Several phase I/II clinical trials using such compounds have reported promising, but mostly transient, clinical responses. This underscores the need to further dissect the molecular players of epigenetic mechanisms driving induction, maintenance, and potential reversibility of leukemic state to develop efficient and long-lasting targeted therapeutic strategies.

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  1. Friedrich Miescher Institute for Biomedical Research, CH-4058, Basel, Switzerland

    Antoine H. F. M. Peters

  2. Department Biomedicine, University Hospital Basel, CH-4031, Basel, Switzerland

    Juerg Schwaller

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    Susan M. Gasser

  2. BioMedical Research Co., Ltd., China Novartis Institutes for, Lane 898 Halei Road, Shanghai, 201203, China, People's Republic

    En Li

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Peters, A.H.F.M., Schwaller, J. (2011). Epigenetic Mechanisms in Acute Myeloid Leukemia. In: Gasser, S., Li, E. (eds) Epigenetics and Disease. Progress in Drug Research, vol 67. Springer, Basel. https://doi.org/10.1007/978-3-7643-8989-5_10

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