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Single cell transcriptomc analysis of CD34+ cells from primary myelofibrosis patient

ABSTRACT: We performed single cell RNA sequencing by means of 10X Genomics platform of CD34+ hematopoietic stem/progenitor cells (HSPCs) from primary myelofibrosis (PMF). Cells were isolated through immunomagnetic selection from frozen PBMCs coming from one patient with PMF who evolved to Acute Myeloid Leukemia (AML). Three timepoints were considered: chronic phase (Time1), after 8 months of Ruxolitinib treatment (Time2) and after 11 months of Ruxolitinib treatment at AML diagnosis (Time3). The main purpose of this project was to reconstruct the composition of the neoplastic clone in terms of HSPCs subpopulations at different time-points during disease evolution and to study changes in gene expression within each cell cluster over time.

ORGANISM(S): Homo sapiens

PROVIDER: GSE153319 | GEO | 2021/02/16

REPOSITORIES: GEO

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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.

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Single cell transcriptomc analysis of CD34+ cells from primary myelofibrosis patient

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