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3695 Whole Transcriptome Analysis Identifies Distinct Gene Expression Profiles between SF3B1mut and SF3B1wt Myelodysplastic Syndrome with Ring Sideroblasts

Program: Oral and Poster Abstracts
Session: 637. Myelodysplastic Syndromes — Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Epidemiology, Clinical Practice (Health Services and Quality), Health Outcomes Research, Workforce, Diseases, Myeloid Malignancies
Monday, December 13, 2021, 6:00 PM-8:00 PM

Gabriele Todisco, MD1,2*, Maria Creignou1*, Elsa Bernard, PhD3*, Ann-Charlotte Björklund1*, Pedro Luis Moura, PhD4*, Monika Jansson1*, David Chang1*, Sigita Venckute1*, Gunilla Walldin1*, Luca Malcovati, MD5, Bianca Tesi, MD6*, Teresa Mortera-Blanco, PhD1*, Indira Barbosa, BMA1*, Elli Papaemmanuil, PhD3 and Eva Hellstrom Lindberg, MD, PhD1

1Center for Hematology and Regenerative Medicine, Department of Medicine (MedH), Karolinska Institutet, Huddinge, Sweden
2University of Pavia, Department of Molecular Medicine, Pavia, Italy
3Computational Oncology Service, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
4Center for Hematology and Regenerative Medicine, Department of Medicine (MedH), Karolinska Institutet, Huddinge, Stockholm, Sweden
5Department of Molecular Medicine & Hematology Oncology, University of Pavia & IRCCS Policlinico S. Matteo Foundation, Pavia, Italy
6Department of Clinical Genetics, Karolinska Institutet, Stockholm, Sweden

Background and aims – The 2016 revised WHO classification incorporated somatic mutation in SF3B1 spliceosome gene within the diagnostic criteria of myelodysplastic syndrome (MDS) with ring sideroblasts (RS). However, SF3B1wt MDS-RS display significantly different clinical features and outcome from those of SF3B1mut MDS-RS. Recently, the recognition of SF3B1-mutant MDS as a distinct nosologic entity has been proposed to overcome this limitation.

Methods - To evaluate the biological relevance of this proposal, we studied a consecutive cohort of 132 MDS with RS >5% using a pangenomic approach (targeted-DNA sequencing, genome-wide copy number variation analysis and bulk RNA-sequencing of CD34+ bone marrow mononuclear cells). 16 age-matched healthy individuals and 43 MDS-SLD/MLD negative for both splicing mutation and RS were included in this study as controls.

Results – Unsupervised clustering analysis based on mutation profiles identified two major clusters predicted by SF3B1 mutation (87 MDS-RS-SF3B1mut and 45 MDS-RS-SF3B1wt). The most recurrently mutated genes in MDS-RS-SF3B1wt were TP53(40%), SRSF2(38%), TET2 (33%), ASXL1 (21%) and DNMT3A (12%). SRSF2 and TP53 mutations were found to be mutually exclusive with SF3B1 (p-value <0.05), whereas no difference was found in TET2, DNMT3A and ASXL1 frequencies between MDS-RS-SF3B1mut and MDS-RS-SF3B1wt subgroups. TP53-mutated MDS-RS exhibited shorter overall survival (median 1.3 years, log-rank p-value<0.0001) compared to SF3B1mut (median 7.6 years), SRSF2mut (median 3.4 years) and MDS-RS without the abovementioned aberrations (median 4.4 years). Notably, allelic imbalances analysis of oncogenic variants identified a significant enrichment of TP53 biallelic inactivation in MDS-RS-SF3B1wt (64% vs 0, p<0.01).

Differential gene expression analysis results were incorporated into a specific expression signature highly predictive of MDS-RS-SF3B1mut and MDS-RS-SF3B1wt subgroups (Figure 1). The resulting gene clusters were classified in RS-specific genes (cluster 1 and 2) and SF3B1-specific genes (cluster 3 and 4). RS-specific genes comprising heme and hypoxia genes were enriched (Figure 2AB) and correlated with RS percentage (p<0.01). Pathway analysis revealed a specific downregulation of adhesion molecules and an upregulation of G-protein coupled receptor signaling molecules in MDS-RS-SF3B1mut. Among SF3B1-specific genes (Figure 2CD), we confirmed ABCB7 downregulation and identified new molecular targets that may concur to the pathophysiology of SF3B1-driven myeloid neoplasms.

Conclusions - This study contributes to unveil molecular features of SF3B1-mutant MDS and provides further evidence to support recognition of somatic SF3B1 mutation as a disease-defining genetic lesion.

Disclosures: Papaemmanuil: Isabl Technologies: Divested equity in a private or publicly-traded company in the past 24 months; Kyowa Hakko Kirin Pharma: Consultancy.

*signifies non-member of ASH