Identification of novel myelodysplastic syndromes prognostic subgroups by integration of inflammation, cell-type composition, and immune signatures in the bone marrow

Gerlevik, S.; Hama, S.; Seymen, N.; Mumtaz, W.; Thompson, I. R.; Jalili, S. R.; Kaya, D. E.; Iacoangeli, A.; Pellagatti, A.; Boultwood, J.; Napolitani, G.; Mufti, G. J.; Karimi, M. M.

doi:10.1101/2024.03.11.584361

bioRxiv · 10.1101/2024.03.11.584361

Identification of novel myelodysplastic syndromes prognostic subgroups by integration of inflammation, cell-type composition, and immune signatures in the bone marrow

Gerlevik, S.·Hama, S.·Seymen, N.·Mumtaz, W.·Thompson, I. R.·Jalili, S. R.·Kaya, D. E.·Iacoangeli, A.·Pellagatti, A.·Boultwood, J.·Napolitani, G.·Mufti, G. J.·Karimi, M. M.

View original source ↗Export metadata ↓

Abstract

Mutational profiles of Myelodysplastic syndromes (MDS) have established that a relatively small number of genetic aberrations, including SF3B1 and SRSF2 spliceosome mutations, lead to specific phenotypes and prognostic subgrouping. We performed a Multi-Omics Factor Analysis (MOFA) on two published MDS cohorts of bone marrow mononuclear cells (BMMNCs) and CD34+ cells with three data modalities (clinical, genotype, and transcriptomics). Seven different views, including immune profile, inflammation/aging, Retrotransposon (RTE) expression, and cell-type composition, were derived from these modalities to identify the latent factors with significant impact on MDS prognosis. SF3B1 was the only mutation among 13 mutations in the BMMNC cohort, indicating a significant association with high inflammation. This trend was also observed to a lesser extent in the CD34+ cohort. Interestingly, the MOFA factor representing the inflammation shows a good prognosis for MDS patients with high inflammation. In contrast, SRSF2 mutant cases show a granulocyte-monocyte progenitor (GMP) pattern and high levels of senescence, immunosenescence, and malignant myeloid cells, consistent with their poor prognosis. Furthermore, MOFA identified RTE expression as a risk factor for MDS. This work elucidates the efficacy of our integrative approach to assess the MDS risk that goes beyond all the scoring systems described thus far for MDS.

Source connections

Published article ↗

Explore related subjects

genomics Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Gerlevik, S., Hama, S., Seymen, N., Mumtaz, W., Thompson, I. R., Jalili, S. R., Kaya, D. E., Iacoangeli, A., Pellagatti, A., Boultwood, J., Napolitani, G., Mufti, G. J., Karimi, M. M.. 2024-03-13. Identification of novel myelodysplastic syndromes prognostic subgroups by integration of inflammation, cell-type composition, and immune signatures in the bone marrow. https://doi.org/10.1101/2024.03.11.584361

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Genome-wide diversity across 130 years reveals drastic post-bottleneck genetic erosion in a recovering population of golden eagles (Aquila chrysaetos)

Many wild populations have experienced severe human-induced declines, but the genetic consequences of such bottlenecks are often poorly understood. In Finland, as well as in many other countries, golden eagles were heavily persecuted during the 19th-20th centuries, disappearing from southern regions and reaching their lowest population size in the 1950-1960s. Although conservation efforts facilitated demographic recovery, the long-term genomic consequences of the bottleneck remained unknown. Here, we used whole-genome sequencing data spanning 136 years to evaluate patterns of genetic diversity in 26 Finnish golden eagles before, during, and after the mid-20th century bottleneck. We found substantial loss of genetic variation, including an 82% reduction in genome-wide heterozygosity, a 42% decline in nucleotide diversity, a 67% reduction in Watterson's theta, and a substantial loss of variable sites. Analyses of the site frequency spectrum and Tajima's D confirmed historical population contraction, and runs of homozygosity analysis indicated elevated post-bottleneck inbreeding. These results indicate strong genetic erosion in Finnish golden eagles despite the census size recovery. Therefore, incorporating genomic indicators in conservation monitoring and performing regional assessments are necessary to guide management and preserve biodiversity in line with the Global Biodiversity Framework's goal of maintaining genetic variation.

genomics↗

bioRxiv2026

Long-read analysis of complete human 5S rDNA arrays reveals a zoned organization with two-state unit methylation linked to chromatin architecture

Despite the fundamental importance of the 5S ribosomal DNA (rDNA) to all cellular life, the landscape of its units by position along its array has remained poorly understood. Here, recent telomere-to-telomere long-read sequencing is used to resolve 5S rDNA arrays from flank to flank and to follow the state of each unit along single molecules. The array is zoned at both the sequence and the epigenetic level. Notably, methylation is bimodal at the level of the unit, and the combination of low-methylation and high-methylation units gives rise to the overall methylation pattern of the array. Moreover, the average number of low-methylation units remains relatively constant regardless of array length. Chromatin fiber sequencing (Fiber-seq) data further show that low-methylation units are more accessible, have lower nucleosome occupancy and are more frequently footprinted at the TFIIIB-binding site, consistent with analyses of ATAC-seq and ChIP-seq data from cell lines. Across species, this pattern is shared among apes, whereas other species show diverse patterns. These results provide a unit-resolved view of the human 5S rDNA array and reveal a zone-specific organization of unit methylation that is associated with chromatin architecture.

genomics↗

bioRxiv2026

Using Oyster Genomics to Understand Human Health

As sessile filter feeders that experience continuous environmental exposure, oysters, particularly Crassostrea virginica, offer a unique opportunity to understand how environmental exposure alters the genome and influence health. Furthermore, oysters must be sorted by size for market value for premium size and taste. However, it requires intensive labor, specialized equipment (tumblers), and is susceptible to environmental risks like pollution. Therefore, it is desirable to produce uniform oysters without machines. However, limitations in the previous reference genome [2] have constrained our understanding of how genes are organized and maintained in oyster populations. To this end, we harvested 240 adult oysters in same location, 120 extremely large size and 120 extremely small, controlled with all confounding factors such as age and water temperature. We perform a genome wise associate study (GWAS) using next generation whole genome sequencing, aiming to discover genomic regions associated with oyster size. Using PacBio HiFi, Illumina, and Hi-C technologies, we generated a 99.7% complete chromosome-level genome assembly for C. virginica (NCBI RefSeq GCF_053477285.1) [75]. We identified a ~13 Mb region on chromosome 1 uniquely expanded in C. virginica and enriched for innate immune and stress-response genes. To evaluate whether these structural features are reflected at the population level, we then conducted a k-mer analysis. This revealed differential sequence patterns by size, including enrichment of bacterial DNA in smaller individuals and host variation at the RNF213 locus within this region. By highlighting genome structure as a mediator of immune resilience, this work supports the use of oysters as sentinels to advance out understanding of how the dynamic reassembly of the genome due to environmental exposures influence health in human populations.

genomics↗