Single-cell analyses reveal megakaryocyte-biased hematopoiesis in myelofibrosis and identify mutant clone-specific targets
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 perfor...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Elsevier
2020
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| _version_ | 1826285793258242048 |
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| author | Psaila, B Wang, G Rodriguez-Meira, A Li, R Heuston, EF Murphy, L Yee, D Hitchcock, IS Sousos, N O'Sullivan, J Anderson, S Senis, YA Weinberg, OK Calicchio, ML NIH Intramural Sequencing Center Iskander, D Royston, D Milojkovic, D Roberts, I Bodine, DM Thongjuea, S Mead, AJ |
| author_facet | Psaila, B Wang, G Rodriguez-Meira, A Li, R Heuston, EF Murphy, L Yee, D Hitchcock, IS Sousos, N O'Sullivan, J Anderson, S Senis, YA Weinberg, OK Calicchio, ML NIH Intramural Sequencing Center Iskander, D Royston, D Milojkovic, D Roberts, I Bodine, DM Thongjuea, S Mead, AJ |
| author_sort | Psaila, B |
| collection | OXFORD |
| description | 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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| first_indexed | 2024-03-07T01:34:08Z |
| format | Journal article |
| id | oxford-uuid:9492c159-cf08-454c-808e-515e17208b62 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:34:08Z |
| publishDate | 2020 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | oxford-uuid:9492c159-cf08-454c-808e-515e17208b622022-03-26T23:40:24ZSingle-cell analyses reveal megakaryocyte-biased hematopoiesis in myelofibrosis and identify mutant clone-specific targetsJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:9492c159-cf08-454c-808e-515e17208b62EnglishSymplectic ElementsElsevier2020Psaila, BWang, GRodriguez-Meira, ALi, RHeuston, EFMurphy, LYee, DHitchcock, ISSousos, NO'Sullivan, JAnderson, SSenis, YAWeinberg, OKCalicchio, MLNIH Intramural Sequencing CenterIskander, DRoyston, DMilojkovic, DRoberts, IBodine, DMThongjuea, SMead, AJMyelofibrosis 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. |
| spellingShingle | Psaila, B Wang, G Rodriguez-Meira, A Li, R Heuston, EF Murphy, L Yee, D Hitchcock, IS Sousos, N O'Sullivan, J Anderson, S Senis, YA Weinberg, OK Calicchio, ML NIH Intramural Sequencing Center Iskander, D Royston, D Milojkovic, D Roberts, I Bodine, DM Thongjuea, S Mead, AJ Single-cell analyses reveal megakaryocyte-biased hematopoiesis in myelofibrosis and identify mutant clone-specific targets |
| title | Single-cell analyses reveal megakaryocyte-biased hematopoiesis in myelofibrosis and identify mutant clone-specific targets |
| title_full | Single-cell analyses reveal megakaryocyte-biased hematopoiesis in myelofibrosis and identify mutant clone-specific targets |
| title_fullStr | Single-cell analyses reveal megakaryocyte-biased hematopoiesis in myelofibrosis and identify mutant clone-specific targets |
| title_full_unstemmed | Single-cell analyses reveal megakaryocyte-biased hematopoiesis in myelofibrosis and identify mutant clone-specific targets |
| title_short | Single-cell analyses reveal megakaryocyte-biased hematopoiesis in myelofibrosis and identify mutant clone-specific targets |
| title_sort | single cell analyses reveal megakaryocyte biased hematopoiesis in myelofibrosis and identify mutant clone specific targets |
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