TY - JOUR
T1 - A critical role of RUNX1 in governing megakaryocyte-primed hematopoietic stem cell differentiation
AU - Wang, Chen
AU - Tu, Zhaowei
AU - Cai, Xiongwei
AU - Wang, Weinan
AU - Davis, Ashely K.
AU - Nattamai, Kalpana
AU - Paranjpe, Aditi
AU - Dexheimer, Philip
AU - Wu, Jianqiang
AU - Huang, Frank Lei
AU - Geiger, Hartmut
AU - Huang, Gang
AU - Zheng, Yi
N1 - Funding Information:
This work was partially supported by grants U54 DK126108 from the National Institute of Diabetes, Digestion and Kidney Diseases, R01 CA234038 and R01 CA204895 from the National Cancer Institute, and R01 HL147536 from the National Institute of Heart, Lung and Blood of the National Institutes of Health, and a Cancer-Free Kids award.
Publisher Copyright:
© 2023 by The American Society of Hematology.
PY - 2023/6/13
Y1 - 2023/6/13
N2 - As a transcription factor in the RUNT domain core-binding factor family, RUNX1 is crucial in multiple stages of hematopoiesis, and its mutation can cause familial platelet disorder with a predisposition to acute myeloid leukemia. Previous work has established that RUNX1 is involved in the maturation of megakaryocytes (MKs) and the production of platelets. Recent studies have shown that there exists a subpopulation of hematopoietic stem cells (HSCs) with relatively high expression of von Willebrand factor and CD41 at the apex of the HSC hierarchy, termed MK-HSCs, which can give rise to MKs without going through the traditional differentiation trajectory from HSC via MPP (multipotent progenitors) and MEP (megakaryocyte–erythroid progenitor). Here, by using Runx1F/FMx1-Cre mouse model, we discovered that the MK-HSC to MK direct differentiation can occur within 1 cell division, and RUNX1 is an important regulator in the process. Runx1 knockout results in a drastic decrease in platelet counts and a severe defect in the differentiation from MK-HSCs to MKs. Single cell RNA sequencing (RNAseq) analysis shows that MK-HSCs have a distinct gene expression signature compared with non-MK–HSCs, and Runx1 deletion alters the platelet and MK-related gene expression in MK-HSCs. Furthermore, bulk RNAseq and Cut&Run analyses show that RUNX1 binds to multiple essential MK or platelet developmental genes, such as Spi1, Selp, and Itga2b and regulates their expressions in MK-HSCs. Thus, by modulating the expression of MK-related genes, RUNX1 governs the direct differentiation from MK-HSCs to MKs and platelets.
AB - As a transcription factor in the RUNT domain core-binding factor family, RUNX1 is crucial in multiple stages of hematopoiesis, and its mutation can cause familial platelet disorder with a predisposition to acute myeloid leukemia. Previous work has established that RUNX1 is involved in the maturation of megakaryocytes (MKs) and the production of platelets. Recent studies have shown that there exists a subpopulation of hematopoietic stem cells (HSCs) with relatively high expression of von Willebrand factor and CD41 at the apex of the HSC hierarchy, termed MK-HSCs, which can give rise to MKs without going through the traditional differentiation trajectory from HSC via MPP (multipotent progenitors) and MEP (megakaryocyte–erythroid progenitor). Here, by using Runx1F/FMx1-Cre mouse model, we discovered that the MK-HSC to MK direct differentiation can occur within 1 cell division, and RUNX1 is an important regulator in the process. Runx1 knockout results in a drastic decrease in platelet counts and a severe defect in the differentiation from MK-HSCs to MKs. Single cell RNA sequencing (RNAseq) analysis shows that MK-HSCs have a distinct gene expression signature compared with non-MK–HSCs, and Runx1 deletion alters the platelet and MK-related gene expression in MK-HSCs. Furthermore, bulk RNAseq and Cut&Run analyses show that RUNX1 binds to multiple essential MK or platelet developmental genes, such as Spi1, Selp, and Itga2b and regulates their expressions in MK-HSCs. Thus, by modulating the expression of MK-related genes, RUNX1 governs the direct differentiation from MK-HSCs to MKs and platelets.
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U2 - 10.1182/bloodadvances.2022008591
DO - 10.1182/bloodadvances.2022008591
M3 - Article
C2 - 36661340
AN - SCOPUS:85164925443
SN - 2473-9529
VL - 7
SP - 2590
EP - 2605
JO - Blood Advances
JF - Blood Advances
IS - 11
ER -