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Review
. 2020 Apr 8;12(4):907.
doi: 10.3390/cancers12040907.

Estrogen Receptors Alpha and Beta in Acute Myeloid Leukemia

Alessia Roma  1 , Paul A Spagnuolo  1
Affiliations
Review

Estrogen Receptors Alpha and Beta in Acute Myeloid Leukemia

Alessia Roma et al. Cancers (Basel). .

Abstract

Estrogen receptor (ER) signaling has been widely studied in a variety of solid tumors, where the differential expression of ERα and ERβ subtypes can impact prognosis. ER signaling has only recently emerged as a target of interest in acute myeloid leukemia (AML), an aggressive hematological malignancy with sub-optimal therapeutic options and poor clinical outcomes. In a variety of tumors, ERα activation has proliferative effects, while ERβ targeting results in cell senescence or death. Aberrant ER expression and hypermethylation have been characterized in AML, making ER targeting in this disease of great interest. This review describes the expression patterns of ERα and ERβ in AML and discusses the differing signaling pathways associated with each of these receptors. Furthermore, we assess how these signaling pathways can be targeted by various selective estrogen receptor modulators to induce AML cell death. We also provide insight into ER targeting in AML and discuss pending questions that require further study.

Keywords: acute myeloid leukemia (AML); diosmetin; estrogen receptors (ERs); estrogens; genistein; quercetin.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The role of estrogen receptors in hematopoiesis and acute myeloid leukemia (AML). In hematopoiesis, the activation of ERα by estradiol or tamoxifen increased proliferation and decreased self-renewal of primitive long-term hematopoietic stem cells (LT-HSC). The upregulation of c-myc and downregulation of c-kit upon ERα activation contributes to this phenotype. Multipotent progenitors (MPP) undergo apoptosis while ERα-mediated activation of IRF4 encourages dendritic cell differentiation. Additionally, ERα-mediated inhibition of GATA1 increases erythropoiesis while the ERβ-mediated activation of GATA1 results in increased megakaryocyte polyploidization to produce platelets. In malignancy, lymphoid-related cancers predominantly express the ERβ subtype and its activation inhibits tumor growth. The knockdown of ESR2, the gene encoding ERβ, leads to a myeloproliferative disease in mice resembling chronic myeloid leukemia. The possible origins of this disease are unknown and thus symbolized by dashed arrows. In AML, the DNA hypermethylation of ESR1 is prominent among patients and results in decreased transcription of ERα. ERα hypermethylation often co-occurs with the methylation of other tumor suppressor genes, which also influences patient prognosis and the response to hypomethylating agents. A subset of AML patients also express increased ERβ compared to ERα, and it has been shown that this subset would best be targeted by an ERβ agonist.
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References

    1. O’Donnell M.R., Tallman M.S., Abboud C.N., Altman J.K., Appelbaum F.R., Arber D.A., Attar E., Borate U., Coutre S.E., Damon L.E., et al. Acute myeloid leukemia, version 2.2013. J. Natl. Compr. Cancer Netw. 2013;11:1047–1055. doi: 10.6004/jnccn.2013.0127. - DOI - PMC - PubMed
    1. Dohner H., Weisdorf D.J., Bloomfield C.D. Acute Myeloid Leukemia. N. Engl. J. Med. 2015;373:1136–1152. doi: 10.1056/NEJMra1406184. - DOI - PubMed
    1. Notta F., Zandi S., Takayama N., Dobson S., Gan O.I., Wilson G., Kaufmann K.B., McLeod J., Laurenti E., Dunant C.F., et al. Distinct routes of lineage development reshape the human blood hierarchy across ontogeny. Science. 2016;351:aab2116. doi: 10.1126/science.aab2116. - DOI - PMC - PubMed
    1. Bonnet D., Dick J.E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med. 1997;3:730–737. doi: 10.1038/nm0797-730. - DOI - PubMed
    1. Patel J.P., Gönen M., Figueroa M.E., Fernandez H., Sun Z., Racevskis J., Van Vlierberghe P., Dolgalev I., Thomas S., Aminova O., et al. Prognostic relevance of integrated genetic profiling in acute myeloid leukemia. N. Engl. J. Med. 2012;366:1079–1089. doi: 10.1056/NEJMoa1112304. - DOI - PMC - PubMed

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