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Review
. 2019 Sep 9:9:867.
doi: 10.3389/fonc.2019.00867. eCollection 2019.

Towards a Better Understanding of Cohesin Mutations in AML

Sergi Cuartero  1   2   3 , Andrew J Innes  1   4 , Matthias Merkenschlager  1
Affiliations
Review

Towards a Better Understanding of Cohesin Mutations in AML

Sergi Cuartero et al. Front Oncol. .

Abstract

Classical driver mutations in acute myeloid leukemia (AML) typically affect regulators of cell proliferation, differentiation, and survival. The selective advantage of increased proliferation, improved survival, and reduced differentiation on leukemia progression is immediately obvious. Recent large-scale sequencing efforts have uncovered numerous novel AML-associated mutations. Interestingly, a substantial fraction of the most frequently mutated genes encode general regulators of transcription and chromatin state. Understanding the selective advantage conferred by these mutations remains a major challenge. A striking example are mutations in genes of the cohesin complex, a major regulator of three-dimensional genome organization. Several landmark studies have shown that cohesin mutations perturb the balance between self-renewal and differentiation of hematopoietic stem and progenitor cells (HSPC). Emerging data now begin to uncover the molecular mechanisms that underpin this phenotype. Among these mechanisms is a role for cohesin in the control of inflammatory responses in HSPCs and myeloid cells. Inflammatory signals limit HSPC self-renewal and drive HSPC differentiation. Consistent with this, cohesin mutations promote resistance to inflammatory signals, and may provide a selective advantage for AML progression. In this review, we discuss recent progress in understanding cohesin mutations in AML, and speculate whether vulnerabilities associated with these mutations could be exploited therapeutically.

Keywords: AML; cohesin; hematopoiesis; inflammation; interferon; leukemia.

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Figures

Figure 1
Figure 1
Classical and non-classical AML mutations. (A) Classical AML mutations deregulate proliferation, survival and differentiation pathways and provide an obvious selective advantage to AML. (B) Novel AML mutations include mutations in transcription and chromatin regulators and their selective advantage is less obvious.
Figure 2
Figure 2
Cohesin regulates the balance between self-renewal and differentiation. Cohesin controls expression of pro-inflammatory genes that promote HSPC differentiation. In cohesin-mutant AML, inflammatory gene expression is downregulated, increasing resistance to differentiation and favoring HSPC self-renewal.
See this image and copyright information in PMC

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References

    1. Saultz J, Garzon R. Acute myeloid leukemia: a concise review. J Clin Med. (2016) 5:33. 10.3390/jcm5030033 - DOI - PMC - PubMed
    1. Daver N, Schlenk RF, Russell NH, Levis MJ. Targeting FLT3 mutations in AML: review of current knowledge and evidence. Leukemia. (2019) 33:299–312. 10.1038/s41375-018-0357-9 - DOI - PMC - PubMed
    1. Ward AF, Braun BS, Shannon KM. Targeting oncogenic Ras signaling in hematologic malignancies. Blood. (2012) 120:3397–406. 10.1182/blood-2012-05-378596 - DOI - PMC - PubMed
    1. Vousden KH, Prives C. Blinded by the light: the growing complexity of p53. Cell. (2009) 137:413–31. 10.1016/j.cell.2009.04.037 - DOI - PubMed
    1. Pabst T, Mueller BU, Zhang P, Radomska HS, Narravula S, Schnittger S, et al. . Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-α (C/EBPα), in acute myeloid leukemia. Nat Genet. (2001) 27:263–70. 10.1038/85820 - DOI - PubMed