Single-cell analyses reveal megakaryocyte-biased hematopoiesis in myelofibrosis and identify mutant clone-specific targets
| Autor: | Olga K. Weinberg, Rong Li, Ian S. Hitchcock, Daniel Yee, Elisabeth F. Heuston, Bethan Psaila, Stacie M. Anderson, Yotis A. Senis, Guanlin Wang, David M. Bodine, Nikolaos Sousos, Jennifer O'Sullivan, Irene Roberts, Dragana Milojkovic, Monica L. Calicchio, Lauren Murphy, Daniel Royston, Adam J. Mead, Alba Rodriguez-Meira, Supat Thongjuea, Deena Iskander |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
Megakaryocyte differentiation myeloproliferative neoplasm SUSCEPTIBILITY 0302 clinical medicine Megakaryocyte RNA-SEQ Receptors Immunologic NIH Intramural Sequencing Center 11 Medical and Health Sciences Aged 80 and over 0303 health sciences PROGENITORS High-Throughput Nucleotide Sequencing Cell Differentiation single-cell multi-omics Middle Aged medicine.anatomical_structure DIFFERENTIATION platelets Female immunotherapy Single-Cell Analysis Life Sciences & Biomedicine STEM-CELLS megakaryopoiesis Megakaryocytes Biochemistry & Molecular Biology MYELOPROLIFERATIVE NEOPLASMS bone marrow Biology Article G6B TARGET-seq 03 medical and health sciences medicine Humans Progenitor cell GENOME-WIDE ASSOCIATION Myelofibrosis Molecular Biology Myeloproliferative neoplasm 030304 developmental biology Megakaryopoiesis Aged Science & Technology CYSTIC-FIBROSIS IDENTIFICATION fibrosis Cell Biology 06 Biological Sciences medicine.disease Hematopoietic Stem Cells Hematopoiesis Gene Expression Regulation Multipotent Stem Cell Primary Myelofibrosis Mutation Cancer research IDIOPATHIC PULMONARY-FIBROSIS Bone marrow 030217 neurology & neurosurgery Developmental Biology |
| Zdroj: | 492.e8 Molecular Cell |
| Popis: | Summary 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. Graphical Abstract Highlights • Single-cell-omics demonstrate megakaryocyte-biased hematopoiesis in myelofibrosis (MF) • Megakaryocyte progenitors (MkPs) show high expression of a fibrosis signature in MF • MkPs are heterogeneous in MF with aberrant metabolic and inflammatory signatures • Targeting aberrant surface G6B expression may selectively ablate the MF clone Myelofibrosis (MF) is characterized by increased numbers of morphologically abnormal megakaryocytes (Mks). Single-cell RNA sequencing of >120,000 hematopoietic stem and progenitor cells demonstrated Mk-biased hematopoiesis across clinical and molecular MF subgroups. Mk progenitors were heterogeneous, with distinct expression of inflammatory mediators. Aberrant surface G6B expression on MF stem and progenitors could allow selective immunotherapeutic targeting of the MF clone. |
| Databáze: | OpenAIRE |
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