PU.1-activated genomic regions define low-risk MDS subsets characterized by immune dysregulation and disease progression
Abstract
Abstract Myelodysplastic syndromes (MDS) are heterogeneous myeloid neoplasms associated with an increased risk of progression to secondary acute myeloid leukemia (sAML). This study investigates the genomic correlates of disease progression in MDS by profiling active genomic regulatory regions and their transcriptional impact using H3K27ac chromatin immunoprecipitation–sequencing and RNA-sequencing analysis on CD34+ bone marrow progenitors cells isolated from a prospective cohort of 86 and 357 patients, respectively. Our analysis revealed distinct patterns of genomic region activation and transcriptional regulation across different disease stages such as low-risk MDS, high-risk MDS, and sAML. Unexpectedly, unsupervised clustering revealed a subset of patients with low-risk MDS 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 natural killer cell 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 significantly reduced overall survival. Functional studies demonstrated 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 patients with low-risk MDS to progression to high-risk MDS and, ultimately, sAML.
Article Details
Authors (23)
Veronica Vallelonga
1Department of Experimental Oncology, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Francesco Gandolfi
1Department of Experimental Oncology, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Matteo Zampini
2Humanitas Research Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Elena Riva
Giulia Maggioni
2Humanitas Research Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Denise Ventura
2Humanitas Research Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Elena Saba
2Humanitas Research Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Alberto Termanini
4Human Technopole, Milan, Italy
Sara Polletti
1Department of Experimental Oncology, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Elena Prosperini
1Department of Experimental Oncology, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Laura Crisafulli
2Humanitas Research Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Alessia Campagna
2Humanitas Research Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Ivan Ferrari
Nicole Pinocchio
2Humanitas Research Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Gabriele Todisco
Silvia Pedretti
1Department of Experimental Oncology, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Michela Calvi
2Humanitas Research Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Clara Di Vito
2Humanitas Research Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Domenico Mavilio
Nico Mitro
1Department of Experimental Oncology, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy
Francesca Ficara
Matteo Giovanni Della Porta
Serena Ghisletti
1Department of Experimental Oncology, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico, Milan, Italy