Transcriptional control and signal transduction, cell cycle

Determinants and role of chromatin organization in acute leukemia

Abstract

DNA is compacted into higher order structures that have major implications in gene regulation. These structures allow for long-range interactions of DNA elements, such as the association of promoters with their cognate enhancers. In recent years, mutations in genes that control these structures, including the cohesin-complex and the insulator-binding protein CTCF, have been found in a spectrum of hematologic disorders, and especially in acute leukemias. Cohesin and CTCF are critical for mediating looping and establishing boundaries within chromatin. Cells that harbor mutations in these genes display aberrant chromatin architecture and resulting differences in gene expression that contribute to leukemia initiation and progression. Here, we provide detailed discussion of the nature of 3D interactions and the way that they are disrupted in acute leukemia. Continued research in this area will provide new insights into the mechanisms of leukemogenesis and may shed light on novel treatment strategies.

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Fig. 1: Working model for the role of CTCF and cohesion in chromatin looping.
Fig. 2: Models of looping alteration schemes observed in leukemias.
Fig. 3: The MYC locus as a model of chromatin looping and associated mechanisms in acute leukemia.

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Acknowledgements

This review was supported in part by the NIH (CA101774 to JDC, R01CA248770 and U54CA193419 to PN, and 5T32GM008152-33 to CF by the NIH-NIGMS training grant), the NSF (1830968 (PN) and the Zell Foundation (to PN).

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CF, SR, JDC, and PN wrote the review.

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Fang, C., Rao, S., Crispino, J.D. et al. Determinants and role of chromatin organization in acute leukemia. Leukemia (2020). https://doi.org/10.1038/s41375-020-0981-z

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