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

Change log
Tong, Jingyuan 
Sun, Ting 
Ma, Shihui 
Zhao, Yanhong 
Ju, Mankai 

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.

JAK2V617F, MPN, hematopoietic stem cells, heterogeneity, inflammation, interferon, megakaryocyte lineage priming, pathogenesis, single cell RNA-Seq, therapeutic response, Hematopoietic Stem Cells, Humans, Janus Kinase 2, Mutation, Myeloproliferative Disorders, Neoplasms, Polycythemia Vera
Journal Title
Cell Stem Cell
Conference Name
Journal ISSN
Volume Title
Elsevier BV
Cancer Research UK (21762)
Wellcome Trust (203151/Z/16/Z)
Medical Research Council (MC_PC_17230)
Wellcome Trust (104710/Z/14/Z)