PU.1-ACTIVATED GENOMIC REGIONS DEFINE LOW-RISK MDS SUBSETS CHARACTERIZED BY IMMUNE DYSREGULATION AND DISEASE PROGRESSION

Myelodysplastic syndromes (MDS) are heterogeneous myeloid neoplasms with an increased risk of progression to secondary acute myeloid leukemia (sAML). This study investigates the genomic signatures associated to disease progression in MDS. To this end, we profiled active genomic regulatory regions and their transcriptional impact through H3K27ac ChIP-seq and RNA-seq analysis on CD34+ bone marrow progenitors cells isolated from a prospective cohort of 357 patients. Our analysis revealed distinct patterns of genomic region activation and transcriptional regulation across different disease stages (low-risk MDS, high-risk MDS and sAML). Unexpectedly, unsupervised clustering revealed a subset of low-risk MDS patients displaying regulatory and transcriptional profiles similar to those of high-risk MDS and sAML, highlighting early molecular events that may predispose patients to disease progression. This subset is characterized by PU.1 genomic occupancy in regions linked to immune and inflammatory responses, increased T-cell and NK activation, and a higher frequency of SRSF2 mutations. Clinically, patients in this group exhibit greater susceptibility to infections and cardiovascular events, along with an elevated risk of disease progression, resulting in a significantly reduced overall survival. Functional studies demonstrate that PU.1 inhibition suppresses MDS cell proliferation and clonogenicity, as impaired PU.1 binding inhibits the activation of key transcriptional programs involved in disease advancement. Collectively, these findings identify epigenetic factors that predispose low-risk MDS patients to progression into high-risk MDS and, ultimately, sAML. Moreover, they provide proof of concept for targeting PU.1 as a potential strategy to prevent disease progression in low-risk MDS.

Grantor dc:publisher

Università degli Studi di Milano

Year dc:date

2025

Author dc:creator

• VALLELONGA, VERONICA

Contributors dc:contributor

• supervisore: S. M. L. Ghisletti ; co-tutor: S. Minucci ; PhD coordinator: D. Pasini
• V. Vallelonga
• GHISLETTI, SERENA MARIA LUISA
• PASINI, DIEGO

• Epigenetic
• Functional Genomic
• Myelodysplastic Syndromes (MDS)
• Transcription factor
• PU.1
• Acute Myeloid Leukemia (AML)
• Settore MEDS-02/A - Patologia generale

Statement dc:rights

• info:eu-repo/semantics/embargoedAccess
• license:Creative commons
• license uri:http://creativecommons.org/licenses/by-sa/4.0/

Language dc:language

eng

Handle dc:identifier

https://hdl.handle.net/2434/1197876

OAI identifier oai:identifier

oai:air.unimi.it:2434/1197876