The functional role of estrogen receptor alpha (ERα) in AML; a new potential therapeutic target for the treatment of inv (16) and MLL-rearranged acute myeloid leukemia

Dijk, A.D. van (Anneke) (2016) The functional role of estrogen receptor alpha (ERα) in AML; a new potential therapeutic target for the treatment of inv (16) and MLL-rearranged acute myeloid leukemia. thesis, Medicine.

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Abstract

Acute myeloid leukemia (AML) is the most life threatening cancer in children. Last decades treatment strategies have been improved based on the information of cytogenetic abnormalities and mutational analysis of AML patient samples. Despite intensive chemotherapy, AML remains a leading cause of cancer related death. The (inv16) chromosomal translocation is one of the most frequent genetic alternation in AML. Although these patients have favorable prognosis, still 30% of inv(16) AML patients relapse. Therefore, new therapeutic options are needed. Recently, it has been shown that kinome profiling is able to give more insights in active signal transduction pathways for specific subgroups AML and point out interesting signaling hubs as well as new potential druggable targets. With this technique the gap between newly designed drugs and AML may be bridged. In this project, we found higher phosphorylation of ERα_s167 in inv(16) AML patients compared to CN-AML by using kinome profiling array. Direct protein-protein interaction analysis confirmed ERα as signaling hubs in inv(16) AML. ERα is a regulator of transcriptional processes. Classical mechanism of ERα action involves β-estradiol binding to receptors in the nucleus, after which the receptor dimerize and bind to DNA in the promoters of target genes. Target genes of ERα are known to play a role in tumor proliferation, as showed in breast and gynecological cancers and therefore is ERα an interesting target to investigate. We performed in vitro experiments to evaluate the role of ERα for the first time in AML and found protein expression of total and phosphorylated ERα in inv(16) celline ME-1 and inv(16) AML patients. We also proved ligand-dependent phosphorylation of ERα by β-estradiol in AML. Moreover, MLL-rearranged patients showed also high protein expression of ERα_s167 and therefore we extented our project with a specific MLL celline THP-1. We hypothesized that inhibition of ERα would reduce cell proliferation for inv(16) and MLL-rearranged AML. A remarkable decrease in cell proliferation is discovered when cells are treated with 1-10 μM 4-hydroxytamoxifen, a small molecule inhibitor of ERα. Furthermore, chemotherapeutic treatment with stimulation of estrogen receptor showed less chemosensitivity. Our results conclude that ERα may play an important role in AML proliferation. Therefore, we propose future experiments to combine treatment of chemotherapeutic drug with ERα inhibitor.

Item Type:	Thesis (Thesis)
Supervisor name:	Supervisor: and Bont, Prof. Dr. E.S.J.M. de and Second supervisor: and Mahmud, Dr. H. and Department of Pediatric Oncology/Hematology and Beatrix Children’s Hospital, University Medical Center Groni and University of Groningen
Faculty:	Medical Sciences
Date Deposited:	25 Jun 2020 10:46
Last Modified:	25 Jun 2020 10:46
URI:	https://umcg.studenttheses.ub.rug.nl/id/eprint/728

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