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Cited by 185Myeloproliferative Neoplasms: Diagnosis and TreatmentAcute Myeloid Leukemia ResearchPlatelet Disorders and Treatments

Single-Cell Analyses Reveal Megakaryocyte-Biased Hematopoiesis in Myelofibrosis and Identify Mutant Clone-Specific Targets

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Psaila, Bethan, Wang, Guanlin, Rodriguez-Meira, Alba, Li, Rong, Heuston, Elisabeth F., Murphy, Lauren, Yee, Daniel, Hitchcock, Ian S. +13 more·2020·Molecular Cell
DOI 10.1016/j.molcel.2020.04.008PMC PMC7217381

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Abstract

Myelofibrosis 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.

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  • Other RFX members such as RFX1 and RFX8 have been demonstrated to regulate MHC class II expression.

    “Although RFX2/3 are not well characterized in hematopoiesis, other RFX members such as RFX1 and RFX8 have been demonstrated to regulate MHC class II expression 35-37 .”

    From Type 1 interferon perturbates clonal competition by reshaping human blood development (2026) · cites this paper as [37]

    The Results passages on myelofibrosis progenitors and transcription-factor expression (page numbers unavailable) do not address regulation of MHC class II by RFX1 or RFX8. Searches for those factors and for MHC class II regulation found no passage in our copy that speaks to the claim. (LLM, conf=0.72)

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Authors
Psaila, B., Wang, G., Rodriguez-Meira, A., Li, R., Heuston, E. F., Murphy, L., Yee, D., Hitchcock, I. S., Sousos, N., O’Sullivan, J., Anderson, S., Senis, Y. A., Weinberg, O. K., Calicchio, M. L., Iskander, D., Royston, D., Milojkovic, D., Roberts, I., Bodine, D. M., Thongjuea, S., & Mead, A. J.
Affiliations
  • National Institutes of Health (US)
  • University of Oxford (GB)
  • University of York (GB)
  • Inserm (FR)
  • Boston Children's Hospital (US)
  • Hammersmith Hospital (GB)
Corresponding author
  • Psaila, Bethan
  • Thongjuea, Supat
  • Mead, Adam J.
ORCID
Venue
Molecular Cell
Publisher
Elsevier BV
Published
2020-05
Volume
78
Issue
3
Pages
477-492.e8
ISSN
1097-2765 (ISSN-L)
DOI
10.1016/j.molcel.2020.04.008
PMC
PMC7217381
OpenAlex
W3022009389
Cited by
185
References
12
Citations by year
2026: 29 · 2025: 30 · 2024: 27 · 2023: 23 · 2022: 30 · 2021: 37 · 2020: 8 · 2019: 1
FWCI
12.68
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Cell (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • White Rose Research Online (University of Leeds, The University of Sheffield, University of York) (acceptedVersion)
  • HAL (submittedVersion)
  • Spiral (Imperial College London) (submittedVersion, cc-by)
Funders
  • Cancer Research UK Advanced Clinician Scientist Fellowship
  • CRUK Innovation Award
  • Wellcome Career Development Fellowship
  • Academy of Medical Sciences Award
  • L’Oréal-UNESCO Women in Science Award
  • Medical Research Council
  • Senior Clinical Fellowship
  • CRUK Senior Cancer Research Fellowship
  • Bloodwise (LAB282)
  • Cancer Research UK DPhil Prize Studentship
  • MRC John Fell Fund award
  • MRC Molecular Haematology Unit core award
Topics
  • Health Sciences › Medicine › Genetics › Myeloproliferative Neoplasms: Diagnosis and Treatment
  • Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
  • Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
Keywords
myelofibrosis, megakaryopoiesis, hematopoiesis, hematopoietic stem and progenitor cells, immunotherapy targets, fibrosis, single-cell multi-omics, megakaryocyte progenitors, clonal expansion
MeSH terms
Aged, Aged, 80 and over, Cell Differentiation, Female, Gene Expression Regulation, Hematopoiesis, Hematopoietic Stem Cells, Humans, Male, Megakaryocytes, Middle Aged, Mutation, Receptors, Immunologic, Primary Myelofibrosis, Single-Cell Analysis, High-Throughput Nucleotide Sequencing

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