PI3 kinase alpha and delta promote hematopoietic stem cell activation
Many cytokines and chemokines that are important for hematopoiesis activate the PI3K signaling pathway. Because this pathway is frequently mutated and activated in cancer, PI3K inhibitors have been developed for the treatment of several malignancies, and are now being tested in the clinic in combination with chemotherapy. However, the role of PI3K in adult hematopoietic stem cells (HSCs), particularly during hematopoietic stress, is still unclear. We previously showed that the individual PI3K catalytic isoforms P110α or P110β have dispensable roles in HSC function, suggesting redundancy between PI3K isoforms in HSCs. We now demonstrate that simultaneous deletion of P110α and P110δ in double knockout (DKO) HSCs uncovers their redundant requirement in HSC cycling after 5-fluorouracil (5-FU) chemotherapy administration. In contrast, DKO HSCs are still able to exit quiescence in response to other stress stimuli, such as LPS. We found that DKO HSCs and progenitors have impaired sensing of inflammatory signals ex vivo, and that levels of IL1-β and MIG are higher in the bone marrow after LPS than after 5-FU administration. Furthermore, exogenous in vivo administration of IL1-β can induce cell cycle entry of DKO HSCs. Our findings have important clinical implications for the use of PI3K inhibitors in combination with chemotherapy.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2019 |
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| Erschienen: |
2019 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:5 |
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| Enthalten in: |
JCI insight - 5(2019) vom: 23. Mai |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Hemmati, Shayda [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 20.07.2020 Date Revised 22.12.2021 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1172/jci.insight.125832 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM29739083X |
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| 100 | 1 | |a Hemmati, Shayda |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a PI3 kinase alpha and delta promote hematopoietic stem cell activation |
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| 500 | |a Date Completed 20.07.2020 | ||
| 500 | |a Date Revised 22.12.2021 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Many cytokines and chemokines that are important for hematopoiesis activate the PI3K signaling pathway. Because this pathway is frequently mutated and activated in cancer, PI3K inhibitors have been developed for the treatment of several malignancies, and are now being tested in the clinic in combination with chemotherapy. However, the role of PI3K in adult hematopoietic stem cells (HSCs), particularly during hematopoietic stress, is still unclear. We previously showed that the individual PI3K catalytic isoforms P110α or P110β have dispensable roles in HSC function, suggesting redundancy between PI3K isoforms in HSCs. We now demonstrate that simultaneous deletion of P110α and P110δ in double knockout (DKO) HSCs uncovers their redundant requirement in HSC cycling after 5-fluorouracil (5-FU) chemotherapy administration. In contrast, DKO HSCs are still able to exit quiescence in response to other stress stimuli, such as LPS. We found that DKO HSCs and progenitors have impaired sensing of inflammatory signals ex vivo, and that levels of IL1-β and MIG are higher in the bone marrow after LPS than after 5-FU administration. Furthermore, exogenous in vivo administration of IL1-β can induce cell cycle entry of DKO HSCs. Our findings have important clinical implications for the use of PI3K inhibitors in combination with chemotherapy | ||
| 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 | 4 | |a Research Support, U.S. Gov't, Non-P.H.S. | |
| 650 | 4 | |a Cell stress | |
| 650 | 4 | |a Hematology | |
| 650 | 4 | |a Hematopoietic stem cells | |
| 650 | 4 | |a Signal transduction | |
| 650 | 7 | |a Antineoplastic Agents |2 NLM | |
| 650 | 7 | |a Enzyme Inhibitors |2 NLM | |
| 650 | 7 | |a Lipopolysaccharides |2 NLM | |
| 650 | 7 | |a Protein Isoforms |2 NLM | |
| 650 | 7 | |a Class I Phosphatidylinositol 3-Kinases |2 NLM | |
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| 700 | 1 | |a Sinclair, Taneisha |e verfasserin |4 aut | |
| 700 | 1 | |a Tong, Meng |e verfasserin |4 aut | |
| 700 | 1 | |a Bartholdy, Boris |e verfasserin |4 aut | |
| 700 | 1 | |a Okabe, Rachel O |e verfasserin |4 aut | |
| 700 | 1 | |a Ames, Kristina |e verfasserin |4 aut | |
| 700 | 1 | |a Ostrodka, Leanne |e verfasserin |4 aut | |
| 700 | 1 | |a Haque, Tamanna |e verfasserin |4 aut | |
| 700 | 1 | |a Kaur, Imit |e verfasserin |4 aut | |
| 700 | 1 | |a Mills, Taylor S |e verfasserin |4 aut | |
| 700 | 1 | |a Agarwal, Anupriya |e verfasserin |4 aut | |
| 700 | 1 | |a Pietras, Eric M |e verfasserin |4 aut | |
| 700 | 1 | |a Zhao, Jean J |e verfasserin |4 aut | |
| 700 | 1 | |a Roberts, Thomas M |e verfasserin |4 aut | |
| 700 | 1 | |a Gritsman, Kira |e verfasserin |4 aut | |
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