| Literature DB >> 33621485 |
Jingyuan Tong1, Ting Sun2, Shihui Ma1, Yanhong Zhao3, Mankai Ju2, Yuchen Gao2, Ping Zhu1, Puwen Tan4, Rongfeng Fu2, Anqi Zhang5, Ding Wang3, Di Wang3, Zhijian Xiao3, Jiaxi Zhou1, Renchi Yang2, Stephen J Loughran6, Juan Li6, Anthony R Green6, Emery H Bresnick7, Dong Wang8, Tao Cheng9, Lei Zhang10, Lihong Shi11.
Abstract
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.Entities:
Keywords: JAK2V617F; MPN; hematopoietic stem cells; heterogeneity; inflammation; interferon; megakaryocyte lineage priming; pathogenesis; single cell RNA-Seq; therapeutic response
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Year: 2021 PMID： 33621485 DOI： 10.1016/j.stem.2021.01.018
Source DB: PubMed Journal: Cell Stem Cell ISSN： 1875-9777 Impact factor: 24.633