Ubiquitin-dependent degradation of CDK2 drives the therapeutic differentiation of AML by targeting PRDX2
Ying, M., Shao, X., Jing, H., Liu, Y., Qi, X., Cao, J., Chen, Y., Xiang, S., Song, H., Hu, R., Wei, G., Yang, B., He, Q.
American Society of Hematology (ASH)
Published 2018
American Society of Hematology (ASH)
Published 2018
| Publication Date: |
2018-06-15
|
|---|---|
| Publisher: |
American Society of Hematology (ASH)
|
| Print ISSN: |
0006-4971
|
| Electronic ISSN: |
1528-0020
|
| Topics: |
Biology
Medicine
|
| Keywords: |
Myeloid Neoplasia
|
| Published by: |
| _version_ | 1836398971113701376 |
|---|---|
| autor | Ying, M., Shao, X., Jing, H., Liu, Y., Qi, X., Cao, J., Chen, Y., Xiang, S., Song, H., Hu, R., Wei, G., Yang, B., He, Q. |
| beschreibung | A distinct hallmark of acute myeloid leukemia (AML) is the arrest of leukemic myeloblasts at an immature stage of development. Therapies that overcome differentiation arrest have emerged as a powerful strategy for treating AML, but targeting leukemia differentiation remains challenging, mainly because of an incomplete mechanistic understanding of the process. Here, we unveil a new role for cyclin-dependent kinase 2 (CDK2) in blocking myeloid differentiation in AML. We show that among several interphase CDK, only CDK2 undergoes ubiquitin-dependent proteasome degradation, which is accompanied by AML cell differentiation. By using the yeast 2-hybrid system and functional analyses, KLHL6 was identified as a specific E3 ubiquitin ligase regulating the degradation of CDK2. Importantly, inhibiting CDK2, but not other cyclin-dependent kinases CDK1/4/6, effectively induced granulocytic differentiation in AML cell lines and 5 major subtypes of primary patient-derived AML samples. Mechanistically, CDK2 depletion led to the reactivation of differentiation pathway translation, and the differentiation blockade function of CDK2 may be achieved directly by maintaining the activity of PRDX2. Finally, CDK2 depletion arrested tumor growth of AML cells in nude mice and extended survival in both AML cell line and PDX-AML cells derived xenograft mouse models. Thus, our work not only provides experimental evidence for validating CDK2 as a potential therapeutic target for differentiation, but also uncovers the biological function of the CDK2-PRDX2 axis in blocking AML differentiation. |
| citation_standardnr | 6283211 |
| datenlieferant | ipn_articles |
| feed_id | 310 |
| feed_publisher | American Society of Hematology (ASH) |
| feed_publisher_url | http://www.hematology.org/ |
| insertion_date | 2018-06-15 |
| journaleissn | 1528-0020 |
| journalissn | 0006-4971 |
| publikationsjahr_anzeige | 2018 |
| publikationsjahr_facette | 2018 |
| publikationsjahr_intervall | 7984:2015-2019 |
| publikationsjahr_sort | 2018 |
| publisher | American Society of Hematology (ASH) |
| quelle | Blood |
| relation | http://www.bloodjournal.org/cgi/content/short/131/24/2698?rss=1 |
| schlagwort | Myeloid Neoplasia |
| search_space | articles |
| shingle_author_1 | Ying, M., Shao, X., Jing, H., Liu, Y., Qi, X., Cao, J., Chen, Y., Xiang, S., Song, H., Hu, R., Wei, G., Yang, B., He, Q. |
| shingle_author_2 | Ying, M., Shao, X., Jing, H., Liu, Y., Qi, X., Cao, J., Chen, Y., Xiang, S., Song, H., Hu, R., Wei, G., Yang, B., He, Q. |
| shingle_author_3 | Ying, M., Shao, X., Jing, H., Liu, Y., Qi, X., Cao, J., Chen, Y., Xiang, S., Song, H., Hu, R., Wei, G., Yang, B., He, Q. |
| shingle_author_4 | Ying, M., Shao, X., Jing, H., Liu, Y., Qi, X., Cao, J., Chen, Y., Xiang, S., Song, H., Hu, R., Wei, G., Yang, B., He, Q. |
| shingle_catch_all_1 | Ubiquitin-dependent degradation of CDK2 drives the therapeutic differentiation of AML by targeting PRDX2 Myeloid Neoplasia A distinct hallmark of acute myeloid leukemia (AML) is the arrest of leukemic myeloblasts at an immature stage of development. Therapies that overcome differentiation arrest have emerged as a powerful strategy for treating AML, but targeting leukemia differentiation remains challenging, mainly because of an incomplete mechanistic understanding of the process. Here, we unveil a new role for cyclin-dependent kinase 2 (CDK2) in blocking myeloid differentiation in AML. We show that among several interphase CDK, only CDK2 undergoes ubiquitin-dependent proteasome degradation, which is accompanied by AML cell differentiation. By using the yeast 2-hybrid system and functional analyses, KLHL6 was identified as a specific E3 ubiquitin ligase regulating the degradation of CDK2. Importantly, inhibiting CDK2, but not other cyclin-dependent kinases CDK1/4/6, effectively induced granulocytic differentiation in AML cell lines and 5 major subtypes of primary patient-derived AML samples. Mechanistically, CDK2 depletion led to the reactivation of differentiation pathway translation, and the differentiation blockade function of CDK2 may be achieved directly by maintaining the activity of PRDX2. Finally, CDK2 depletion arrested tumor growth of AML cells in nude mice and extended survival in both AML cell line and PDX-AML cells derived xenograft mouse models. Thus, our work not only provides experimental evidence for validating CDK2 as a potential therapeutic target for differentiation, but also uncovers the biological function of the CDK2-PRDX2 axis in blocking AML differentiation. Ying, M., Shao, X., Jing, H., Liu, Y., Qi, X., Cao, J., Chen, Y., Xiang, S., Song, H., Hu, R., Wei, G., Yang, B., He, Q. American Society of Hematology (ASH) 0006-4971 00064971 1528-0020 15280020 |
| shingle_catch_all_2 | Ubiquitin-dependent degradation of CDK2 drives the therapeutic differentiation of AML by targeting PRDX2 Myeloid Neoplasia A distinct hallmark of acute myeloid leukemia (AML) is the arrest of leukemic myeloblasts at an immature stage of development. Therapies that overcome differentiation arrest have emerged as a powerful strategy for treating AML, but targeting leukemia differentiation remains challenging, mainly because of an incomplete mechanistic understanding of the process. Here, we unveil a new role for cyclin-dependent kinase 2 (CDK2) in blocking myeloid differentiation in AML. We show that among several interphase CDK, only CDK2 undergoes ubiquitin-dependent proteasome degradation, which is accompanied by AML cell differentiation. By using the yeast 2-hybrid system and functional analyses, KLHL6 was identified as a specific E3 ubiquitin ligase regulating the degradation of CDK2. Importantly, inhibiting CDK2, but not other cyclin-dependent kinases CDK1/4/6, effectively induced granulocytic differentiation in AML cell lines and 5 major subtypes of primary patient-derived AML samples. Mechanistically, CDK2 depletion led to the reactivation of differentiation pathway translation, and the differentiation blockade function of CDK2 may be achieved directly by maintaining the activity of PRDX2. Finally, CDK2 depletion arrested tumor growth of AML cells in nude mice and extended survival in both AML cell line and PDX-AML cells derived xenograft mouse models. Thus, our work not only provides experimental evidence for validating CDK2 as a potential therapeutic target for differentiation, but also uncovers the biological function of the CDK2-PRDX2 axis in blocking AML differentiation. Ying, M., Shao, X., Jing, H., Liu, Y., Qi, X., Cao, J., Chen, Y., Xiang, S., Song, H., Hu, R., Wei, G., Yang, B., He, Q. American Society of Hematology (ASH) 0006-4971 00064971 1528-0020 15280020 |
| shingle_catch_all_3 | Ubiquitin-dependent degradation of CDK2 drives the therapeutic differentiation of AML by targeting PRDX2 Myeloid Neoplasia A distinct hallmark of acute myeloid leukemia (AML) is the arrest of leukemic myeloblasts at an immature stage of development. Therapies that overcome differentiation arrest have emerged as a powerful strategy for treating AML, but targeting leukemia differentiation remains challenging, mainly because of an incomplete mechanistic understanding of the process. Here, we unveil a new role for cyclin-dependent kinase 2 (CDK2) in blocking myeloid differentiation in AML. We show that among several interphase CDK, only CDK2 undergoes ubiquitin-dependent proteasome degradation, which is accompanied by AML cell differentiation. By using the yeast 2-hybrid system and functional analyses, KLHL6 was identified as a specific E3 ubiquitin ligase regulating the degradation of CDK2. Importantly, inhibiting CDK2, but not other cyclin-dependent kinases CDK1/4/6, effectively induced granulocytic differentiation in AML cell lines and 5 major subtypes of primary patient-derived AML samples. Mechanistically, CDK2 depletion led to the reactivation of differentiation pathway translation, and the differentiation blockade function of CDK2 may be achieved directly by maintaining the activity of PRDX2. Finally, CDK2 depletion arrested tumor growth of AML cells in nude mice and extended survival in both AML cell line and PDX-AML cells derived xenograft mouse models. Thus, our work not only provides experimental evidence for validating CDK2 as a potential therapeutic target for differentiation, but also uncovers the biological function of the CDK2-PRDX2 axis in blocking AML differentiation. Ying, M., Shao, X., Jing, H., Liu, Y., Qi, X., Cao, J., Chen, Y., Xiang, S., Song, H., Hu, R., Wei, G., Yang, B., He, Q. American Society of Hematology (ASH) 0006-4971 00064971 1528-0020 15280020 |
| shingle_catch_all_4 | Ubiquitin-dependent degradation of CDK2 drives the therapeutic differentiation of AML by targeting PRDX2 Myeloid Neoplasia A distinct hallmark of acute myeloid leukemia (AML) is the arrest of leukemic myeloblasts at an immature stage of development. Therapies that overcome differentiation arrest have emerged as a powerful strategy for treating AML, but targeting leukemia differentiation remains challenging, mainly because of an incomplete mechanistic understanding of the process. Here, we unveil a new role for cyclin-dependent kinase 2 (CDK2) in blocking myeloid differentiation in AML. We show that among several interphase CDK, only CDK2 undergoes ubiquitin-dependent proteasome degradation, which is accompanied by AML cell differentiation. By using the yeast 2-hybrid system and functional analyses, KLHL6 was identified as a specific E3 ubiquitin ligase regulating the degradation of CDK2. Importantly, inhibiting CDK2, but not other cyclin-dependent kinases CDK1/4/6, effectively induced granulocytic differentiation in AML cell lines and 5 major subtypes of primary patient-derived AML samples. Mechanistically, CDK2 depletion led to the reactivation of differentiation pathway translation, and the differentiation blockade function of CDK2 may be achieved directly by maintaining the activity of PRDX2. Finally, CDK2 depletion arrested tumor growth of AML cells in nude mice and extended survival in both AML cell line and PDX-AML cells derived xenograft mouse models. Thus, our work not only provides experimental evidence for validating CDK2 as a potential therapeutic target for differentiation, but also uncovers the biological function of the CDK2-PRDX2 axis in blocking AML differentiation. Ying, M., Shao, X., Jing, H., Liu, Y., Qi, X., Cao, J., Chen, Y., Xiang, S., Song, H., Hu, R., Wei, G., Yang, B., He, Q. American Society of Hematology (ASH) 0006-4971 00064971 1528-0020 15280020 |
| shingle_title_1 | Ubiquitin-dependent degradation of CDK2 drives the therapeutic differentiation of AML by targeting PRDX2 |
| shingle_title_2 | Ubiquitin-dependent degradation of CDK2 drives the therapeutic differentiation of AML by targeting PRDX2 |
| shingle_title_3 | Ubiquitin-dependent degradation of CDK2 drives the therapeutic differentiation of AML by targeting PRDX2 |
| shingle_title_4 | Ubiquitin-dependent degradation of CDK2 drives the therapeutic differentiation of AML by targeting PRDX2 |
| timestamp | 2025-06-30T23:35:33.410Z |
| titel | Ubiquitin-dependent degradation of CDK2 drives the therapeutic differentiation of AML by targeting PRDX2 |
| titel_suche | Ubiquitin-dependent degradation of CDK2 drives the therapeutic differentiation of AML by targeting PRDX2 |
| topic | W WW-YZ |
| uid | ipn_articles_6283211 |