Small molecule inhibition of Dynamin-dependent endocytosis targets multiple niche signals and impairs leukemia stem cells

Cedric S. Tremblay (), Sung Kai Chiu, Jesslyn Saw, Hannah McCalmont, Veronique Litalien, Jacqueline Boyle, Stefan E. Sonderegger, Ngoc Chau, Kathryn Evans, Loretta Cerruti, Jessica M. Salmon, Adam McCluskey, Richard B. Lock, Phillip J. Robinson, Stephen M. Jane and David J. Curtis
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Cedric S. Tremblay: Monash University
Sung Kai Chiu: Monash University
Jesslyn Saw: Monash University
Hannah McCalmont: University of New South Wales
Veronique Litalien: Monash University
Jacqueline Boyle: Monash University
Stefan E. Sonderegger: Monash University
Ngoc Chau: Children’s Medical Research Institute
Kathryn Evans: University of New South Wales
Loretta Cerruti: Monash University
Jessica M. Salmon: Monash University
Adam McCluskey: University of Newcastle
Richard B. Lock: University of New South Wales
Phillip J. Robinson: Children’s Medical Research Institute
Stephen M. Jane: Monash University
David J. Curtis: Monash University

Nature Communications, 2020, vol. 11, issue 1, 1-18

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-20091-6

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