Are DNA damage response kinases a target for the differentiation treatment of acute myeloid leukemia?

Abstract

Acute myeloid leukemia (AML) is a genetically heterogeneous malignancy characterized by the expansion of hematopoietic stem/progenitor cells (HPCs) blocked at different stages of maturation/differentiation. The poor outcome of AMLs necessitates therapeutic improvement. In AML, genes encoding for myeloid transcription factors, signaling receptors regulating cell proliferation, and epigenetic modifiers can be mutated by somatically acquired genetic mutations or altered by chromosomal translocations. These mutations modify chromatin organization at genes sites regulating HPCs proliferation, terminal differentiation, and DNA repair, contributing to the development and progression of the disease. The reversibility of the epigenetic modifications by drug treatment makes epigenetic changes attractive targets for AML therapeutic intervention. Recent findings underline increased DNA damage and abnormalities in the DNA damage response (DDR) as a critical feature of AML blasts. The DDR preserves cell integrity and must be tightly coordinated with DNA methylation and chromatin remodeling to ensure the accessibility to the DNA of transcription factors and repair enzymes. A crucial role in these events is played by the ataxia telangiectasia mutated (ATM) and ataxia telangiectasia and Rad3-related protein (ATR) kinases, which are hyperactive in AML. Based on these findings, we hypothesize the inhibition of DNA damage kinases as an alternative or complementary strategy for the differentiation treatment of AML as it leads to a reduced ability to repair the DNA damage, and to the inhibition of specific epigenetic modifiers whose function is altered in leukemic cells. © 2018 IUBMB Life, 70(11):1057-1066, 2018.

• Authors: Rosa Pennisi, Jacopo Albanesi, Paolo Ascenzi, Clara Nervi, Alessandra di Masi
• Journal: IUBMB life (IUBMB Life) Vol. 70 Issue 11 Pg. 1057-1066 (11 2018) ISSN: 1521-6551 [Electronic] England
• PMID: 30296357 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2018 International Union of Biochemistry and Molecular Biology.

Chemical References

• Protein Kinase Inhibitors
• ATM protein, human
• ATR protein, human
• Ataxia Telangiectasia Mutated Proteins

Topics

• Ataxia Telangiectasia Mutated Proteins (antagonists & inhibitors)
• Cell Differentiation
• DNA Damage
• DNA Repair
• Humans
• Leukemia, Myeloid, Acute (drug therapy, metabolism, pathology)
• Protein Kinase Inhibitors (therapeutic use)