Investigating novel prognostic groups in MDS and AML identified using the DNA damage repair deficiency gene signature

Abstract

This study investigated the application of the DDRD signature to MDS and AML gene expression datasets. Survival analyses revealed that the DDRD signature is a prognostic tool for AML patients and for MDS patients under 65 years old or have the intermediate-2 risk classification. Differential gene expression analyses revealed immune signalling pathways to be driving the DDRD phenotype in MDS and AML. Expression of two genes from the DDRD signature, MX1 and IFI44L, were found to be independent prognostic biomarkers for AML. MDS and AML in vitro cell models were classified using the DDRD signature and experiments did not uncover a DNA repair defect associated with the DDRD signature classification. Further bioinformatic analyses across multiple AML datasets revealed IFNγ signalling to consistently be the top enriched hallmark in the DDRD+ patient cohort. It was found that DDRD- classified cell models were more sensitive to IFNγ than DDRD+ classified cell models. The study found no conclusive evidence on the disease biology driving the DDRD phenotype in MDS and AML, however, has shed light on new prognostic markers and possible new therapeutic options for patient treatment.

Thesis is embargoed until 31 July 2029.

Date of Award	Jul 2024
Original language	English
Awarding Institution	Queen's University Belfast
Sponsors	MDS UK Patient Support Group
Supervisor	Kienan Savage (Supervisor) & Katrina Lappin (Supervisor)