Imaging dynamic mTORC1 pathway activity in vivo reveals marked shifts that support time-specific inhibitor therapy in AML

Toshihiko Oki, Francois Mercier, Hiroki Kato, Yookyung Jung, Thomas O. McDonald, Joel A. Spencer, Michael C. Mazzola, Nick van Gastel, Charles P. Lin, Franziska Michor, Toshio Kitamura and David T. Scadden ()
Additional contact information
Toshihiko Oki: Massachusetts General Hospital
Francois Mercier: Massachusetts General Hospital
Hiroki Kato: Massachusetts General Hospital
Yookyung Jung: Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital
Thomas O. McDonald: Harvard University
Joel A. Spencer: Harvard University
Michael C. Mazzola: Massachusetts General Hospital
Nick van Gastel: Massachusetts General Hospital
Charles P. Lin: Harvard University
Franziska Michor: Harvard University
Toshio Kitamura: University of Tokyo
David T. Scadden: Massachusetts General Hospital

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract Acute myeloid leukemia (AML) is a high remission, high relapse fatal blood cancer. Although mTORC1 is a master regulator of cell proliferation and survival, its inhibitors have not performed well as AML treatments. To uncover the dynamics of mTORC1 activity in vivo, fluorescent probes are developed to track single cell proliferation, apoptosis and mTORC1 activity of AML cells in the bone marrow of live animals and to quantify these activities in the context of microanatomical localization and intra-tumoral heterogeneity. When chemotherapy drugs commonly used clinically are given to mice with AML, apoptosis is rapid, diffuse and not preferentially restricted to anatomic sites. Dynamic measurement of mTORC1 activity indicated a decline in mTORC1 activity with AML progression. However, at the time of maximal chemotherapy response, mTORC1 signaling is high and positively correlated with a leukemia stemness transcriptional profile. Cell barcoding reveals the induction of mTORC1 activity rather than selection of mTORC1 high cells and timed inhibition of mTORC1 improved the killing of AML cells. These data define the real-time dynamics of AML and the mTORC1 pathway in association with AML growth, response to and relapse after chemotherapy. They provide guidance for timed intervention with pathway-specific inhibitors.

Date: 2021
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DOI: 10.1038/s41467-020-20491-8

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