Single-cell analyses reveal megakaryocyte-biased hematopoiesis in myelofibrosis and identify mutant clone-specific targets
File(s)
Published version
Author(s)
Type
Journal Article
Abstract
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.
Date Issued
2020-05-07
Date Acceptance
2020-04-06
Citation
Molecular Cell, 2020, 78 (3), pp.477-492.e8
ISSN
1097-2765
Publisher
Cell Press
Start Page
477
End Page
492.e8
Journal / Book Title
Molecular Cell
Volume
78
Issue
3
Copyright Statement
© 2020 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
License URL
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000531097700012&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Cell Biology
IDIOPATHIC PULMONARY-FIBROSIS
GENOME-WIDE ASSOCIATION
STEM-CELLS
MYELOPROLIFERATIVE NEOPLASMS
CYSTIC-FIBROSIS
RNA-SEQ
PROGENITORS
DIFFERENTIATION
SUSCEPTIBILITY
IDENTIFICATION
Publication Status
Published
Date Publish Online
2020-05-07