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

Authors :
Daniel Yee
Daniel Royston
Nikolaos Sousos
Lauren Murphy
Rong Li
Jennifer O'Sullivan
Bethan Psaila
Stacie M. Anderson
Adam J. Mead
Irene Roberts
Alba Rodriguez Meira
Dragana Milojkovic
David M. Bodine
Elisabeth F. Heuston
Monica L. Calicchio
Deena Iskander
Guanlin Wang
Supat Thongjuea
Olga K. Weinberg
Ian S. Hitchcock
Yotis A. Senis
Publication Year :
2019
Publisher :
Cold Spring Harbor Laboratory, 2019.

Abstract

SummaryMyelofibrosis 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 50,538 hematopoietic stem/progenitor cells (HSPCs), 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 byJAK2-mutant HSPCs. Myelofibrosis megakaryocyte progenitors were heterogeneous, with distinct expression of fibrosis and proliferation-associated genes and putative therapy targets. We validated the immunoglobulin receptor G6B as a promisingJAK2-mutant clone-specific antigen warranting further development as an immunotherapy target. Our study paves the way for selective targeting of the myelofibrosis clone and more broadly illustrates the power of single-cell multi-omics to discover tumor-specific therapeutic targets and mediators of tissue fibrosis.

Details

Language :
English
Database :
OpenAIRE
Accession number :
edsair.doi.dedup.....c07502d45541060be7c9e0dda38f8045
Full Text :
https://doi.org/10.1101/642819