Single-cell analyses reveal aberrant pathways for megakaryocyte-biased hematopoiesis in myelofibrosis and identify mutant clone-specific targets
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA544104 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9104990.fastq.gz | Fastqsanger.gz | |||
| SRR9105000.fastq.gz | Fastqsanger.gz | |||
| SRR9105010.fastq.gz | Fastqsanger.gz | |||
| SRR9105020.fastq.gz | Fastqsanger.gz | |||
| SRR9105030.fastq.gz | Fastqsanger.gz |
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Project description:Myelofibrosis is a severe myeloproliferative neoplasm characterised 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/progenitor cells (HSPCs), single-cell proteomics, genomics and functional assays. We identified a bias towards megakaryocyte differentiation apparent from early multipotent stem cells in myelofibrosis and associated aberrant molecular signatures. A sub-fraction of myelofibrosis megakaryocyte progenitors (MkP) were transcriptionally similar to healthy-donor MkP but the majority were disease-specific, with distinct populations expressing fibrosis- and proliferation-associated genes. Mutant-clone HSPCs showed 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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Project description:Myelofibrosis is a severe myeloproliferative neoplasm characterised by increased numbers of abnormal bone marrow megakaryocytes that induce progressive fibrosis, destroying the hematopoietic microenvironment. To determine the cellular and molecular basis for aberrant megakaryopoiesis in myelofibrosis, we performed high-throughput single-cell transcriptome profiling of 50,702 hematopoietic stem/progenitor cells (HSPCs), and single-cell proteomics, genomics and functional assays. We identified an aberrant pathway for direct megakaryocyte differentiation from the earliest stages of hematopoiesis in myelofibrosis and associated aberrant molecular signatures, including surface antigens selectively expressed by JAK2-mutant HSPCs. Myelofibrosis megakaryocyte progenitors were heterogeneous, with distinct expression of fibrosis and proliferation-associated genes and putative therapy targets. We validated the integrin G6B as a promising JAK2-mutant clone-specific surface antigen, warranting further development as an immunotherapeutic target. Our study paves the way for selective immunotherapeutic targeting in myelofibrosis and more broadly illustrates the power of single-cell multi-omics to discover tumor-specific therapeutic targets and mediators of tissue fibrosis.
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Project description:Single-Cell Analyses Reveal Megakaryocyte-Biased Hematopoiesis in Myelofibrosis and Identify Mutant Clone-Specific Targets
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Project 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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Project description:Hematopoietic stem cells (HSCs) are defined by their capacity to regenerate all main components of the peripheral blood, but individual HSCs exhibit a range of preferences for generating downstream cell types. Their propensities are thought to be epigenetically encoded, but no differential regulatory mechanisms have been identified. Here, we considered whether DNA methyltransferase 3A (DNMT3A) has a role in determining the differentiation choice of HSCs. We find that the most primitive megakaryocyte-biased HSCs depend most on DNMT3A for efficient hematopoietic regeneration, particularly of the lymphoid lineages. Reduced DNMT3A amplifies the biased HSC behavior. DNMT3A also regulates megakaryocyte and platelet output in part through DNA methylation at key megakaryocyte lineage loci. Together, our findings establish the role of epigenetic regulation in the fate of megakaryocyte-biased HSCs and their downstream progeny and suggest that the outcomes of DNMT3A-mutant clonal hematopoiesis and malignancies might vary depending on the identity of the HSC that acquires the mutation.
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