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

• DOI: 10.1016/j.stem.2021.01.018
• Publication Date: 2021-02-23T02:11:38Z
• Authors: Jingyuan Tong; Ting Sun; Shihui Ma; Yanhong Zhao; Mankai Ju; Yuchen Gao; Ping Zhu; Puwen Tan; Rongfeng Fu; Anqi Zhang; Ding Wang; Di Wang; Zhijian Xiao; Jiaxi Zhou; Renchi Yang; Stephen J. Loughran; Juan Li; Anthony R. Green; Emery H. Bresnick; Dong Wang; Tao Cheng; Lei Zhang; Lihong Shi
• Keywords: Pathogenesis; Hematopoietic stem cell

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