Single-Cell Analyses Reveal Megakaryocyte-Biased Hematopoiesis in Myelofibrosis and Identify Mutant Clone-Specific Targets
Bethan Psaila, Guanlin Wang, Alba Rodríguez-Meira, Rong Li, Elisabeth F. Heuston, Lauren C. Murphy, Daniel Yee, Ian S. Hitchcock, Nikolaos Sousos, Jennifer O’Sullivan, Stacie M. Anderson, Yotis A. Senis, Olga K. Weinberg, Monica L. Calicchio, Deena Iskander, Daniel Royston, Dragana Milojković, Irene Roberts, David M. Bodine, Supat Thongjuea, Adam J. Mead
Abstract
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.