Dataset Information

Single-cell analyses reveal aberrant pathways for megakaryocyte-biased hematopoiesis in myelofibrosis and identify mutant clone-specific targets

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE131593 | GEO | 2020/06/30

REPOSITORIES: GEO

ACCESS DATA

Similar Datasets

Project description:Primary myelofibrosis (PMF) is a Myeloproliferative Neoplasm (MPN) characterized by megakaryocyte hyperplasia, progressive bone marrow fibrosis, extramedullary hematopoiesis and transformation to Acute Myeloid Leukemia (AML). Beginning in early 2005, a number of novel mutations involving JAK2, CALR, MPL, TET2, ASXL1, DNMT3a, CBL, IDH1 and IDH2 have been described in MPNs, depicting a really complex genomic landscape for MPNs. To shed light on the genomic lesions that can contribute to disease phenotype and/or development, we integrated gene expression and copy number signals and identified several genomic abnormalities leading to a concordant alteration in gene expression levels. In particular, copy number gain in the polyamine oxidase (PAOX) gene locus is accompanied by a coordinated transcriptional up-regulation in PMF patients. Inhibition of PAOX resulted in rapid cell death in PMF progenitor cells, but not in normal cells, suggesting that PAOX inhibition could represent a therapeutic strategy to selectively target PMF cells without affecting normal hematopoietic cells’ survival. Moreover, copy number loss in the chromatin modifier HMGXB4 gene correlates with a concomitant transcriptional down-regulation in PMF patients. Interestingly, silencing of HMGXB4 induces megakaryocyte differentiation, while inhibiting erythroid development, in human hematopoietic stem/progenitor cells. These results highlight a previously un-reported, yet potentially interesting role of HMGXB4 in the hematopoietic system suggesting that genomic and transcriptional imbalances of HMGXB4 could contribute to the aberrant expansion of the megakaryocytic lineage that characterize PMF patients. In this study, the authors take advantage of the integrative analysis of gene expression and copy number data to identify the concordant gain/up-regulation of the polyamine oxidase PAOX and the loss/down-regulation of the chromatin modifier HMGXB4. This work sheds light on the influence of genomic abnormalities on gene expression regulation in PMF CD34+ cells and on their contribution to specific features of PMF, such as a hyperplastic megakaryopoiesis.

Dataset Information

Single-cell analyses reveal aberrant pathways for megakaryocyte-biased hematopoiesis in myelofibrosis and identify mutant clone-specific targets

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure