Photo Credit: Artur Plawgo
The intricate interplay between malignant plasma cells and the bone marrow microenvironment has emerged as a focal point in multiple myeloma research, according to authors at the ASH Annual Meeting. Understanding these interactions is crucial for uncovering novel therapeutic strategies, they explained. To deepen this understanding, a comprehensive single-cell transcriptomic atlas of the multiple myeloma bone marrow microenvironment was developed. This atlas integrates coding and noncoding RNA profiles while correlating them with specific cytogenetic abnormalities in myeloma cells. By explaining how noncoding RNAs regulate cellular phenotypes and functions, this study aimed to identify their role in shaping the bone marrow microenvironment and advancing knowledge of disease pathogenesis.
The atlas was constructed using single-cell RNA sequencing data from 481 bone marrow aspirate samples from patients enrolled in the MMRF CoMMpass study. This dataset incorporated whole-genome sequencing and survival data, allowing for correlative analyses between transcriptional profiles, cytogenetic abnormalities, and outcomes. By integrating long and small noncoding RNA transcripts from expanded genomic references, the study provided a comprehensive view of the coding and noncoding transcriptome. Rigorous data processing, clustering, and supervised analysis facilitated high-resolution mapping of immune, plasma, and stromal compartments.
The transcriptomic atlas encompassed over 1.9 million cells, with noncoding RNAs accounting for 46% of the associated genes. Analysis identified 22,102 long noncoding RNAs and 3,112 small noncoding RNAs, highlighting their substantial contribution to cellular diversity. Subclustering within immune compartments revealed that 24-38% of the top differentially expressed genes in each immune subpopulation were noncoding RNAs. These findings underscore the critical role of noncoding RNAs in defining immune subpopulations.
Cytogenetic abnormalities in myeloma cells were significantly associated with variations in immune composition. For example, patients with CCND1 amplification exhibited increased CD4+ central memory T cells and reduced CD8+ cytotoxic T cells. Similarly, 1q21 gain correlated with an increase in TGFβ-stimulated monocytes, while 17p13 deletion was linked to reductions in cytotoxic CD8+ T cells and CD56dim NK cells.
Further analyses identified 14 noncoding RNAs that were differentially expressed across cytogenetic abnormalities, six of which were independently associated with poor overall survival. Interestingly, three of these noncoding RNAs, previously implicated in cancer progression, were newly identified in the context of multiple myeloma. Stratifying patients by these noncoding RNAs revealed pronounced changes in immune composition, such as increased CD4+ regulatory T cells. This supports the hypothesis that noncoding RNAs mediate the impact of myeloma genotypes on the bone marrow microenvironment.
A gene regulatory network analysis provided insights into interactions between coding and noncoding RNAs, illustrating how noncoding RNAs modulate the phenotypic states of both malignant and immune cell populations.
“This study reveals distinct immune subpopulations associated with specific myeloma cell genotypes and highlights the central role of ncRNAs in modulating the phenotypic and functional states of both malignant and non-malignant cells in the MM BMME,” the authors concluded.
“Our findings emphasize the potential of ncRNAs as therapeutic targets and prognostic markers for MM, offering new avenues for research and clinical intervention.”
