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Small molecule inhibition of Dynamin-dependent endocytosis targets multiple niche signals and impairs leukemia stem cells.
- Source :
-
Nature communications [Nat Commun] 2020 Dec 04; Vol. 11 (1), pp. 6211. Date of Electronic Publication: 2020 Dec 04. - Publication Year :
- 2020
-
Abstract
- Intensive chemotherapy for acute leukemia can usually induce complete remission, but fails in many patients to eradicate the leukemia stem cells responsible for relapse. There is accumulating evidence that these relapse-inducing cells are maintained and protected by signals provided by the microenvironment. Thus, inhibition of niche signals is a proposed strategy to target leukemia stem cells but this requires knowledge of the critical signals and may be subject to compensatory mechanisms. Signals from the niche require receptor-mediated endocytosis, a generic process dependent on the Dynamin family of large GTPases. Here, we show that Dynole 34-2, a potent inhibitor of Dynamin GTPase activity, can block transduction of key signalling pathways and overcome chemoresistance of leukemia stem cells. Our results provide a significant conceptual advance in therapeutic strategies for acute leukemia that may be applicable to other malignancies in which signals from the niche are involved in disease progression and chemoresistance.
- Subjects :
- Acute Disease
Animals
Cell Line, Tumor
Dynamins metabolism
Humans
Leukemia, Myeloid metabolism
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Mice, Transgenic
Neoplastic Stem Cells drug effects
Stem Cell Niche drug effects
Tumor Microenvironment drug effects
Cyanoacrylates pharmacology
Dynamins antagonists & inhibitors
Endocytosis drug effects
Indoles pharmacology
Leukemia, Myeloid drug therapy
Xenograft Model Antitumor Assays methods
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 11
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 33277497
- Full Text :
- https://doi.org/10.1038/s41467-020-20091-6