Article ; Online: DYRK2 controls a key regulatory network in chronic myeloid leukemia stem cells.
Experimental & molecular medicine
2020 Volume 52, Issue 10, Page(s) 1663–1672
Abstract: Chronic myeloid leukemia is a hematological cancer driven by the oncoprotein BCR-ABL1, and lifelong treatment with tyrosine kinase inhibitors extends patient survival to nearly the life expectancy of the general population. Despite advances in the ... ...
| Abstract | Chronic myeloid leukemia is a hematological cancer driven by the oncoprotein BCR-ABL1, and lifelong treatment with tyrosine kinase inhibitors extends patient survival to nearly the life expectancy of the general population. Despite advances in the development of more potent tyrosine kinase inhibitors to induce a durable deep molecular response, more than half of patients relapse upon treatment discontinuation. This clinical finding supports the paradigm that leukemia stem cells feed the neoplasm, resist tyrosine kinase inhibition, and reactivate upon drug withdrawal depending on the fitness of the patient's immune surveillance. This concept lends support to the idea that treatment-free remission is not achieved solely with tyrosine kinase inhibitors and that new molecular targets independent of BCR-ABL1 signaling are needed in order to develop adjuvant therapy to more efficiently eradicate the leukemia stem cell population responsible for chemoresistance and relapse. Future efforts must focus on the identification of new targets to support the discovery of potent and safe small molecules able to specifically eradicate the leukemic stem cell population. In this review, we briefly discuss molecular maintenance in leukemia stem cells in chronic myeloid leukemia and provide a more in-depth discussion of the dual-specificity kinase DYRK2, which has been identified as a novel actionable checkpoint in a critical leukemic network. DYRK2 controls the activation of p53 and proteasomal degradation of c-MYC, leading to impaired survival and self-renewal of leukemia stem cells; thus, pharmacological activation of DYRK2 as an adjuvant to standard therapy has the potential to induce treatment-free remission. |
|---|---|
| MeSH term(s) | Animals ; Carrier Proteins/metabolism ; Cell Self Renewal/genetics ; Disease Susceptibility ; Energy Metabolism ; Gene Expression Regulation, Leukemic ; Humans ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/etiology ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/metabolism ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology ; Neoplastic Stem Cells/metabolism ; Neoplastic Stem Cells/pathology ; Protein Binding ; Protein Serine-Threonine Kinases/genetics ; Protein Serine-Threonine Kinases/metabolism ; Protein-Tyrosine Kinases/genetics ; Protein-Tyrosine Kinases/metabolism ; Signal Transduction ; Dyrk Kinases |
| Chemical Substances | Carrier Proteins ; Protein-Tyrosine Kinases (EC 2.7.10.1) ; Protein Serine-Threonine Kinases (EC 2.7.11.1) |
| Language | English |
| Publishing date | 2020-10-16 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review |
| ZDB-ID | 1328915-9 |
| ISSN | 2092-6413 ; 1226-3613 ; 0378-8512 |
| ISSN (online) | 2092-6413 |
| ISSN | 1226-3613 ; 0378-8512 |
| DOI | 10.1038/s12276-020-00515-5 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
More links
Kategorien
In stock of ZB MED Cologne/Königswinter
| Zs.A 4775: Show issues | Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG) |
Order via subito
This service is chargeable due to the Delivery terms set by subito. Orders including an article and supplementary material will be classified as separate orders. In these cases, fees will be demanded for each order.