Single-Cell Analyses Reveal Megakaryocyte-Biased Hematopoiesis in Myelofibrosis and Identify Mutant Clone-Specific Targets
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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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Rodriguez-Meira, A., Norfo, R., Wen, S., Chédeville, A. L., Rahman, H., O’Sullivan, J., Wang, G., Louka, E., Kretzschmar, W. W., Paterson, A., et al. (2023) · Nature Genetics · doi:10.1038/s41588-023-01480-1 · Cited by 158 · see citing works
Self-citationType 1 interferon perturbates clonal competition by reshaping human blood development
Lama, C., Isakov, D., Rosenberg, S., Quijada-Álamo, M., Saurty-Seerunghen, M. S., Moein, S., Nozais, M., Abera, T.-A., Sakaguchi, O., Totwani, M., et al. (2026) · Nature Genetics · doi:10.1038/s41588-026-02751-3 · Cited by 3 · see citing works
- 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)
- PMC
- PMC7217381
- OpenAlex
- W3022009389
- Cited by
- 185
- References
- 12
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- FWCI
- 12.68
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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