Single-Cell Analyses Reveal Megakaryocyte-Biased Hematopoiesis in Myelofibrosis and Identify Mutant Clone-Specific Targets

Psaila, Bethan; Wang, Guanlin; Rodríguez-Meira, Alba; Li, Rong; Heuston, Elisabeth F.; Murphy, Lauren C.; Yee, Daniel; Hitchcock, Ian S.; Sousos, Nikolaos; O’Sullivan, Jennifer; Anderson, Stacie M.; Senis, Yotis A.; Weinberg, Olga K.; Calicchio, Monica L.; Iskander, Deena; Royston, Daniel; Milojković, Dragana; Roberts, Irene; Bodine, David M.; Thongjuea, Supat; Mead, Adam J.

doi:10.1016/j.molcel.2020.04.008

Cited by 119 publications

(130 citation statements)

References 89 publications

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“…In addition to modifying HSC proliferation dynamics, the JAK2-V617F mutation also impacts the differentiation dynamics of their progenies. We found that the hematopoietic differentiation hierarchy is largely preserved in ET and PV patients, in contrast to recent observations of aberrant megakaryopoiesis in patients with MF 23 . However, JAK2-mutated HSPCs showed a lineage bias towards the megakaryocyte-erythroid fate and strikingly, we found that the fraction of JAK2mutated cells varied significantly across different progenitor cell populations, suggesting that peripheral blood monitoring may not accurately assess JAK2 mutation burden.…”

Section: Discussioncontrasting

confidence: 99%

“…Using this approach, we detected the JAK2 mutation site (locus encoding codon 617) in at least one transcript in 5-15% of cells (mean 9.5%) in the 7 patient libraries, improving over the existing methods for detecting somatic mutations in single-cell libraries 22,23 . We designated cells in which at least one mutated JAK2 transcript was detected as JAK2-mutant cells.…”

Section: Jak2-mutant Hspcs Exhibit Fate Biasmentioning

confidence: 99%

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Reconstructing the lineage histories and differentiation trajectories of individual cancer cells in JAK2-mutant myeloproliferative neoplasms

Egeren

Escabi

Nguyen

et al. 2020

Preprint

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Some cancers originate from a single mutation event in a single cell. For example, blood cancers known as myeloproliferative neoplasms (MPN) are thought to originate through the acquisition of a driver mutation (most commonly JAK2-V617F) in a hematopoietic stem cell (HSC). However, when the mutation first occurs in individual patients and how it impacts the behavior of HSCs in their native context is not known. Here we quantified the impact of the JAK2-V617F mutation on the proliferation dynamics of HSCs and the differentiation trajectories of their progenies in individual MPN patients. We reconstructed the lineage history of individual HSCs obtained from MPN patients using the patterns of spontaneous somatic mutations accrued in their genomes over time. Strikingly, we found that the JAK2-V617F mutation occurred in a single HSC several decades before MPN diagnosis - at age 9±2 years in a 34-year-old patient, and at age 19±3 years in a 63-year-old patient. For each patient, we inferred the number of mutated HSCs over time and computed their fitness. The population of JAK2-mutated HSCs grew exponentially by 63±15% and 44±13% every year in the two patients, respectively. To contrast the differentiation trajectories of the JAK2-mutated HSCs with those of healthy HSCs, we simultaneously measured the full transcriptome and somatic mutations in single hematopoietic stem and progenitor cells (HSPCs). We found that the fraction of JAK2-mutant HSPCs varied significantly across different myeloid cell types within the same patient. The erythroid progenitor cells were often entirely JAK2-mutant, even when the peripheral blood JAK2-V617F allele burden was low. The novel biological insights uncovered by this work have implications for the prevention and treatment of MPN, as well as the accurate assessment of disease burden in patients. The technology platforms and computational frameworks developed here are broadly applicable to other types of hematological malignancies and cancers.

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Section: Discussioncontrasting

confidence: 99%

Section: Jak2-mutant Hspcs Exhibit Fate Biasmentioning

confidence: 99%

Reconstructing the lineage histories and differentiation trajectories of individual cancer cells in JAK2-mutant myeloproliferative neoplasms

Egeren

Escabi

Nguyen

et al. 2020

Preprint

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“…Recent advances in single-cell approaches have uncovered MPN-specific lineage-trajectories and transcriptional programs. In a recent study Psaila et al combined single-cell RNA sequencing (scRNA-seq) with targeted single-cell mutational analysis on the same MPN cell (TARGET-seq) in MF ( 23 ). They found that JAK2 -mutant MF HSPCs are biased toward the megakaryocyte-lineage from an early HSC stage, where megakaryocytic surface markers (e.g., CD41) are absent ( 23 ).…”

Section: Cellular Contributors To Inflammationmentioning

confidence: 99%

“…In a recent study Psaila et al combined single-cell RNA sequencing (scRNA-seq) with targeted single-cell mutational analysis on the same MPN cell (TARGET-seq) in MF ( 23 ). They found that JAK2 -mutant MF HSPCs are biased toward the megakaryocyte-lineage from an early HSC stage, where megakaryocytic surface markers (e.g., CD41) are absent ( 23 ). In an earlier paper, Nam et al also linked genotyping of expressed genes to their transcriptional profile [Genotyping of Transcriptomes (GoT)] ( 24 ).…”

Section: Cellular Contributors To Inflammationmentioning

confidence: 99%

“…Comprehensive single-cell sequencing is revolutionizing the field of hematology by providing high-resolution profiling of hematopoietic cell populations and by re-defining the hematopoietic hierarchy in normal and malignant hematopoiesis ( 46 – 48 ). Gene set enrichment analysis of megakaryocyte precursors (MkPs) revealed enrichment of inflammatory pathways in MF MkPs as compared to MkPs from healthy donors (HD) ( 23 ). A subset of these MkPs (displaying similar expression profiles between HD and MF MkPs), showed high expression of known mediators of MF (PDGA, CCL5, and CXCL5) ( 23 ).…”

Section: Cellular Contributors To Inflammationmentioning

confidence: 99%

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Remodeling the Bone Marrow Microenvironment – A Proposal for Targeting Pro-inflammatory Contributors in MPN

Jutzi

Mullally

2020

Front. Immunol.

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Philadelphia-negative myeloproliferative neoplasms (MPN) are malignant bone marrow (BM) disorders, typically arising from a single somatically mutated hematopoietic stem cell. The most commonly mutated genes, JAK2 , CALR , and MPL lead to constitutively active JAK-STAT signaling. Common clinical features include myeloproliferation, splenomegaly and constitutional symptoms. This review covers the contributions of cellular components of MPN pathology (e.g., monocytes, megakaryocytes, and mesenchymal stromal cells) as well as cytokines and soluble mediators to the development of myelofibrosis (MF) and highlights recent therapeutic advances. These findings outline the importance of malignant and non-malignant BM constituents to the pathogenesis and treatment of MF.

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Applications of single‐cell multi‐omics sequencing in deep understanding of brain diseases

Zhang¹,

Lü²,

Shen³

2022

Clinical and Translational Dis

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Single-cell sequencing (SCS) revolutionises our understanding of genomic, transcriptomic, proteomic and epigenomic landscapes of cells within the brain. • Single-cell sequencing technologies provide novel data sources available for exploration of brain development and brain-related diseases. • Applications of single-cell multi-omics sequencing facilitate brain intricacy deciphering as well as diagnosis, targeted therapy and prognosis of a wide range of brain diseases.

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Single-Cell Analyses Reveal Megakaryocyte-Biased Hematopoiesis in Myelofibrosis and Identify Mutant Clone-Specific Targets

Cited by 119 publications

References 89 publications

Reconstructing the lineage histories and differentiation trajectories of individual cancer cells in JAK2-mutant myeloproliferative neoplasms

Reconstructing the lineage histories and differentiation trajectories of individual cancer cells in JAK2-mutant myeloproliferative neoplasms

Remodeling the Bone Marrow Microenvironment – A Proposal for Targeting Pro-inflammatory Contributors in MPN

Applications of single‐cell multi‐omics sequencing in deep understanding of brain diseases

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