Hematopoietic Stem Cell Heterogeneity Is Linked to the Initiation and Therapeutic Response of Myeloproliferative Neoplasms

Cell Stem Cell. 2021 Mar 4;28(3):502-513.e6. doi: 10.1016/j.stem.2021.01.018. Epub 2021 Feb 22.


The implications of stem cell heterogeneity for disease pathogenesis and therapy are poorly defined. JAK2V617F+ myeloproliferative neoplasms (MPNs), harboring the same mutation in hematopoietic stem cells (HSCs), display diverse phenotypes, including polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). These chronic malignant disorders are ideal models to analyze the pathological consequences of stem cell heterogeneity. Single-cell gene expression profiling with parallel mutation detection demonstrated that the megakaryocyte (Mk)-primed HSC subpopulation expanded significantly with enhanced potential in untreated individuals with JAK2V617F+ ET, driven primarily by the JAK2 mutation and elevated interferon signaling. During treatment, mutant HSCs were targeted preferentially in the Mk-primed HSC subpopulation. Interestingly, homozygous mutant HSCs were forced to re-enter quiescence, whereas their heterozygous counterparts underwent apoptosis. This study provides important evidence for the association of stem cell heterogeneity with the pathogenesis and therapeutic response of a malignant disease.

Keywords: JAK2V617F; MPN; hematopoietic stem cells; heterogeneity; inflammation; interferon; megakaryocyte lineage priming; pathogenesis; single cell RNA-Seq; therapeutic response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Hematopoietic Stem Cells
  • Humans
  • Janus Kinase 2
  • Mutation / genetics
  • Myeloproliferative Disorders* / drug therapy
  • Neoplasms*
  • Polycythemia Vera* / drug therapy
  • Polycythemia Vera* / genetics


  • Janus Kinase 2