Hematopoietic Stem Cell Heterogeneity Is Linked to the Initiation and Therapeutic Response of Myeloproliferative Neoplasms
| Autor: | Emery H. Bresnick, Shihui Ma, Zhijian Xiao, Lihong Shi, Di Wang, Jiaxi Zhou, Jingyuan Tong, Juan Li, Yanhong Zhao, Mankai Ju, Lei Zhang, Anthony R. Green, Ding Wang, Yuchen Gao, Dong Wang, Anqi Zhang, Stephen J. Loughran, Rongfeng Fu, Ting Sun, Ping Zhu, Tao Cheng, Puwen Tan, Renchi Yang |
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| Přispěvatelé: | Loughran, Stephen [0000-0003-4756-4762], Green, Tony [0000-0002-9795-0218], Apollo - University of Cambridge Repository |
| Rok vydání: | 2021 |
| Předmět: |
MPN
Biology Pathogenesis 03 medical and health sciences 0302 clinical medicine Polycythemia vera Megakaryocyte Neoplasms medicine Genetics Humans JAK2V617F Myelofibrosis Polycythemia Vera 030304 developmental biology 0303 health sciences Myeloproliferative Disorders Essential thrombocythemia pathogenesis therapeutic response single cell RNA-Seq Hematopoietic stem cell Cell Biology interferon Janus Kinase 2 medicine.disease Hematopoietic Stem Cells Haematopoiesis medicine.anatomical_structure megakaryocyte lineage priming inflammation Mutation Cancer research Molecular Medicine Stem cell heterogeneity 030217 neurology & neurosurgery |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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