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Targeting the IRF4 transcriptional network to subvert multiple myeloma

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posted on 2023-06-10, 02:02 authored by Alessandro Agnarelli

Multiple Myeloma (MM) is an incurable hematologic malignancy characterised by abnormal proliferation of plasma cells. Interferon Regulatory Factor 4 (IRF4), a transcription factor essential for immune system regulation and plasma cell differentiation that exerts its action by binding to specific DNA sequences called interferon sequence response element (ISRE), has emerged as the master regulator of an aberrant gene expression programme in MM. Overexpression of IRF4 is found in MM patients’ derived cells, where it is key to their survival. Accumulating evidence suggests that IRF4 and MYC regulate each other in MM cell lines, creating a positive regulatory loop resulting in the proliferation of MM cells. Despite its major role, IRF4 has not been targeted for therapeutic drug discovery programmes. Furthermore, key elements of the mechanism of action of IRF4 in the context of MM, including its ISRE binding strategies, have not been clearly elucidated. The aim of this thesis is to lay the groundwork towards the targeting of IRF4 to subvert MM. To that scope, we pursued several approaches including indirect targeting through IRF4’s upstream epigenetic regulators and IRF4 crystal structural studies to understand the details of DNA binding which are going to be key findings towards IRF4 direct targeting. Given the positive auto regulation loop between MYC and IRF4, we examined the effect of the combination of IRF4 and MYC inhibitors on MM cells. Together with transcription factor network modelling of MM, the results point at additional and yet uncovered regulatory interactions within the IRF4 network. To dissect the mechanism of ISRE binding in MM, we solved the structure of the IRF4 DNA binding domain (DBD) in complex with various ISRE sequences. These data provide key insights into the ISRE binding specificity and affinity in the context of MM and are central to developing a small-molecules drug discovery programme to target IRF4.

History

File Version

  • Published version

Pages

134

Department affiliated with

  • Biochemistry Theses

Qualification level

  • doctoral

Qualification name

  • phd

Language

  • eng

Institution

University off Sussex

Full text available

  • Yes

Supervisor

Dr. Erika J Mancini and Dr. Timothy Chevassut

Legacy Posted Date

2021-12-21

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