Role of c-Myc haploinsufficiency in the maintenance of HSCs in mice
© 2021 by The American Society of Hematology..
This study was conducted to determine the dosage effect of c-Myc on hematopoiesis and its distinct role in mediating the Wnt/β-catenin pathway in hematopoietic stem cell (HSC) and bone marrow niche cells. c-Myc haploinsufficiency led to ineffective hematopoiesis by inhibiting HSC self-renewal and quiescence and by promoting apoptosis. We have identified Nr4a1, Nr4a2, and Jmjd3, which are critical for the maintenance of HSC functions, as previously unrecognized downstream targets of c-Myc in HSCs. c-Myc directly binds to the promoter regions of Nr4a1, Nr4a2, and Jmjd3 and regulates their expression. Our results revealed that Nr4a1 and Nr4a2 mediates the function of c-Myc in regulating HSC quiescence, whereas all 3 genes contribute to the function of c-Myc in the maintenance of HSC survival. Adenomatous polyposis coli (Apc) is a negative regulator of the Wnt/β-catenin pathway. We have provided the first evidence that Apc haploinsufficiency induces a blockage of erythroid lineage differentiation through promoting secretion of IL6 in bone marrow endothelial cells. We found that c-Myc haploinsufficiency failed to rescue defective function of Apc-deficient HSCs in vivo but it was sufficient to prevent the development of severe anemia in Apc-heterozygous mice and to significantly prolong the survival of those mice. Furthermore, we showed that c-Myc-mediated Apc loss induced IL6 secretion in endothelial cells, and c-Myc haploinsufficiency reversed the negative effect of Apc-deficient endothelial cells on erythroid cell differentiation. Our studies indicate that c-Myc has a context-dependent role in mediating the function of Apc in hematopoiesis.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2021 |
|---|---|
| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:137 |
|---|---|
| Enthalten in: |
Blood - 137(2021), 5 vom: 04. Feb., Seite 610-623 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Sheng, Yue [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 21.05.2021 Date Revised 26.02.2024 published: Print Citation Status MEDLINE |
|---|
| doi: |
10.1182/blood.2019004688 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM320994880 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM320994880 | ||
| 003 | DE-627 | ||
| 005 | 20240229152649.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 231225s2021 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1182/blood.2019004688 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1306.xml |
| 035 | |a (DE-627)NLM320994880 | ||
| 035 | |a (NLM)33538795 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Sheng, Yue |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Role of c-Myc haploinsufficiency in the maintenance of HSCs in mice |
| 264 | 1 | |c 2021 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 21.05.2021 | ||
| 500 | |a Date Revised 26.02.2024 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2021 by The American Society of Hematology. | ||
| 520 | |a This study was conducted to determine the dosage effect of c-Myc on hematopoiesis and its distinct role in mediating the Wnt/β-catenin pathway in hematopoietic stem cell (HSC) and bone marrow niche cells. c-Myc haploinsufficiency led to ineffective hematopoiesis by inhibiting HSC self-renewal and quiescence and by promoting apoptosis. We have identified Nr4a1, Nr4a2, and Jmjd3, which are critical for the maintenance of HSC functions, as previously unrecognized downstream targets of c-Myc in HSCs. c-Myc directly binds to the promoter regions of Nr4a1, Nr4a2, and Jmjd3 and regulates their expression. Our results revealed that Nr4a1 and Nr4a2 mediates the function of c-Myc in regulating HSC quiescence, whereas all 3 genes contribute to the function of c-Myc in the maintenance of HSC survival. Adenomatous polyposis coli (Apc) is a negative regulator of the Wnt/β-catenin pathway. We have provided the first evidence that Apc haploinsufficiency induces a blockage of erythroid lineage differentiation through promoting secretion of IL6 in bone marrow endothelial cells. We found that c-Myc haploinsufficiency failed to rescue defective function of Apc-deficient HSCs in vivo but it was sufficient to prevent the development of severe anemia in Apc-heterozygous mice and to significantly prolong the survival of those mice. Furthermore, we showed that c-Myc-mediated Apc loss induced IL6 secretion in endothelial cells, and c-Myc haploinsufficiency reversed the negative effect of Apc-deficient endothelial cells on erythroid cell differentiation. Our studies indicate that c-Myc has a context-dependent role in mediating the function of Apc in hematopoiesis | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, N.I.H., Extramural | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 7 | |a Adenomatous Polyposis Coli Protein |2 NLM | |
| 650 | 7 | |a Interleukin-6 |2 NLM | |
| 650 | 7 | |a Nr4a1 protein, mouse |2 NLM | |
| 650 | 7 | |a Nr4a2 protein, mouse |2 NLM | |
| 650 | 7 | |a Nuclear Receptor Subfamily 4, Group A, Member 1 |2 NLM | |
| 650 | 7 | |a Nuclear Receptor Subfamily 4, Group A, Member 2 |2 NLM | |
| 650 | 7 | |a Proto-Oncogene Proteins c-myb |2 NLM | |
| 650 | 7 | |a adenomatous polyposis coli protein, mouse |2 NLM | |
| 650 | 7 | |a Jumonji Domain-Containing Histone Demethylases |2 NLM | |
| 650 | 7 | |a EC 1.14.11.- |2 NLM | |
| 650 | 7 | |a Kdm6b protein, mouse |2 NLM | |
| 650 | 7 | |a EC 1.5.- |2 NLM | |
| 650 | 7 | |a Poly I-C |2 NLM | |
| 650 | 7 | |a O84C90HH2L |2 NLM | |
| 700 | 1 | |a Ma, Rui |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Chunjie |e verfasserin |4 aut | |
| 700 | 1 | |a Wu, Qiong |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Steven |e verfasserin |4 aut | |
| 700 | 1 | |a Paulsen, Kimberly |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Jiwang |e verfasserin |4 aut | |
| 700 | 1 | |a Ni, Hongyu |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Yong |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Yi |e verfasserin |4 aut | |
| 700 | 1 | |a Qian, Zhijian |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Blood |d 1946 |g 137(2021), 5 vom: 04. Feb., Seite 610-623 |w (DE-627)NLM000014761 |x 1528-0020 |7 nnns |
| 773 | 1 | 8 | |g volume:137 |g year:2021 |g number:5 |g day:04 |g month:02 |g pages:610-623 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1182/blood.2019004688 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 137 |j 2021 |e 5 |b 04 |c 02 |h 610-623 | ||