Abstract
SummaryMyelofibrosis is a severe myeloproliferative neoplasm characterized by increased numbers of abnormal bone marrow megakaryocytes that induce fibrosis, destroying the hematopoietic microenvironment. To determine the cellular and molecular basis for aberrant megakaryopoiesis in myelofibrosis, we performed single-cell transcriptome profiling of 135,929 CD34+ lineage− hematopoietic stem and progenitor cells (HSPCs), single-cell proteomics, genomics, and functional assays. We identified a bias toward megakaryocyte differentiation apparent from early multipotent stem cells in myelofibrosis and associated aberrant molecular signatures. A sub-fraction of myelofibrosis megakaryocyte progenitors (MkPs) are transcriptionally similar to healthy-donor MkPs, but the majority are disease specific, with distinct populations expressing fibrosis- and proliferation-associated genes. Mutant-clone HSPCs have increased expression of megakaryocyte-associated genes compared to wild-type HSPCs, and we provide early validation of G6B as a potential immunotherapy target. Our study paves the way for selective targeting of the myelofibrosis clone and illustrates the power of single-cell multi-omics to discover tumor-specific therapeutic targets and mediators of tissue fibrosis.
Highlights
Advances in single-cell technologies have recently provided new insights into the cellular and molecular diversity and pathological mechanisms underlying many diseases, including cancers, premalignant and non-malignant conditions (Baslan and Hicks, 2017; Owen et al, 2018; Parikh et al, 2019)
To evaluate the pathological role of the expanded megakaryocyte progenitors (MkPs) in driving bone marrow fibrosis, we examined potential mediators of fibrosis among hematopoietic stem and progenitor cells (HSPCs)
We reasoned that aberrant megakaryopoiesis in myelofibrosis is very likely to be caused by aberrant differentiation of HSPCs, rather than proliferation of mature megakaryocytes alone, and that this process might be amenable to therapeutic targeting to ‘‘turn off the supply.’’
Summary
Advances in single-cell technologies have recently provided new insights into the cellular and molecular diversity and pathological mechanisms underlying many diseases, including cancers, premalignant and non-malignant conditions (Baslan and Hicks, 2017; Owen et al, 2018; Parikh et al, 2019). Single-cell resolution uniquely enables the identification of rare cell types and analysis of combinatorial patterns of gene expression, both of which are necessary to reconstruct differentiation trajectories and to accurately define cellular heterogeneity between populations, such as normal and malignant tissues, as well as to identify the mediators of Molecular Cell 78, 477–492, May 7, 2020 a 2020 The Authors. An understanding of the specific cellular populations that mediate fibrosis in a given disease model, their molecular features, and the cellular pathways through which they are generated is necessary for these cells to be therapeutically targeted
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
