Single-cell methods in myeloproliferative neoplasms: old questions, new technologies

Abstract

Myeloproliferative neoplasms (MPN) are a group of clonal, stem cell derived hematopoietic malignancies driven by aberrant JAK/STAT signalling. Although they are genetically simple diseases, MPNs are phenotypically heterogeneous, reflecting underlying intra-tumoral heterogeneity driven by the interplay of genetic and non-genetic factors. As their evolution is determined by factors that enable certain cellular subsets to outcompete others, techniques that resolve cellular heterogeneity at the single-cell level are ideally placed to provide new insights into MPN biology. With these insights comes the potential to uncover new approaches to predict the clinical course and treat these cancers, ultimately improving outcomes for patients. MPNs present a particularly tractable model of cancer evolution, as most patients present in an early disease phase and only a small proportion progress to aggressive disease. Therefore, it is not surprising that many of the groundbreaking technological advances in single-cell omics have been pioneered by their application in MPNs. In this review article, we explore how single-cell approaches have provided transformative insights into MPN disease biology, that are broadly applicable across human cancers, and discuss how these studies might be swiftly translated into clinical pathways and may eventually underpin precision medicine.

Clonal dynamics and copy number variants by single‐cell analysis in leukemic evolution of myeloproliferative neoplasms

“…In conclusion, in this study we have approached the cellular heterogeneity of MPN blast phase exploiting the ideal advantages offered by single‐cell sequencing 29 . Results contribute to the understanding of mutation dynamics linked with clone emergence and predominance, and have highlighted the potential role of copy number variations in the process of blast evolution.…”

“…23,24 Past seminal studies relied on colony picking to highlight relationships between order of mutation acquisition by progenitor cells and clinical phenotype in CP, 25,26 while the study of evolutionary relationships between CP cells and leukemic blasts to elucidate the "patient's journey through cancer" 27 was hampered by intrinsic technical constrains. 28 More recent techniques for SCS generate information of unforeseen granularity regarding clonal architecture and dynamics [29][30][31][32] and also response to therapy. 21,33 By interrogating paired samples collected at CP diagnosis and BP evolution, we analyzed the evolutionary pattern of mutations and CNVs in 10 MPN patients; in one representative case, we contextually generated multimodal data sets informing also on RNA expression and chromatin accessibility.…”

Novel Molecular Insights into Leukemic Evolution of Myeloproliferative Neoplasms: A Single Cell Perspective

“…Given the clonal nature of hematological malignancies, single cell technologies are powerful tools in deciphering single cell molecular heterogeneity to obtain a comprehensive description of neoplastic onset and progression. In particular, new insights on MPN progression have resulted from single cell genomic analysis [ 86 , 87 ].…”

Potential application of bulk RNA sequence in MPNs clinic routine

“…In brief, MPN as an ideal inflammatory tumor model presents typical immune landscape constituted by immune cell, immune cytokine, immune genes, and eventually disease related immune pathways [6]. The dysregulated immune system is tightly related to For the present, advanced technologies such as single cell transcriptomics, mass cytometry, enable us to understand more about the immune landscape in MPNs [32,33], however, these technologies are very expensive and dependent of expertise interpretation [34], it renders these technologies difficult to be generalized in MPNs clinical routine. For the present, flow cytometer analysis is widely used to evaluate phenotypical and functional information about limited immune cell type, still it's not comprehensive; Next gene sequence is used in routine to explore disease highly correlated gene mutations with limited gene number because of cost.…”