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

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. [Display omitted] •Single-cell analyses reveal links between HSC heterogeneity and thrombocythemia•JAK2-mutant HSCs in ET show strong megakaryocyte (Mk) lineage priming•JAK2-mutant HSCs in ET are more sensitive to IFN signaling to Mk differentiation•JAK2-mutant HSCs in ET exhibit distinct signatures upon treatment By single-cell transcriptomic profiling coupled with mutation detection in individuals with myeloproliferative neoplasms (MPNs), Tong et al. found that JAK2V617F+ HSCs exhibited prominent megakaryocyte lineage priming and elevated interferon signaling in essential thrombocythemia (ET). Upon treatment, homozygous mutant HSCs had a quiescent signature, whereas their heterozygous counterparts underwent enhanced apoptosis.