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Oncogenic RAS commandeers amino acid sensing machinery to aberrantly activate mTORC1 in multiple myeloma

Yandan Yang, Thomas Oellerich, Ping Chen, Arnold Bolomsky, Michele Ceribelli, Björn Häupl, George W. Wright, James D. Phelan, Da Wei Huang, James W. Lord, Callie K. Van Winkle, Xin Yu, Jan Wisnieski, James Q. Wang, Frances A. Tosto, Erin Beck, Kelli Wilson, Crystal McKnight, Jameson Travers, Carleen Klumpp-Thomas, Grace A. Smith, Stefania Pittaluga, Irina Maric, Dickran Kazandjian, Craig J. Thomas, Ryan M. Young
doi: https://doi.org/10.1101/2021.11.28.470260
Yandan Yang
1Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD
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Thomas Oellerich
2Department of Medicine II, Heamatology/Oncology, Goethe University, Frankfurt, Germany
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Ping Chen
1Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD
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Arnold Bolomsky
1Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD
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Michele Ceribelli
3Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville MD
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Björn Häupl
2Department of Medicine II, Heamatology/Oncology, Goethe University, Frankfurt, Germany
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George W. Wright
4Biometric Research Branch, DCTD, National Cancer Institute, National Institutes of Health, Bethesda MD
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James D. Phelan
1Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD
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Da Wei Huang
1Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD
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James W. Lord
1Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD
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Callie K. Van Winkle
1Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD
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Xin Yu
1Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD
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Jan Wisnieski
5Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda MD
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James Q. Wang
1Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD
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Frances A. Tosto
3Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville MD
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Erin Beck
3Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville MD
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Kelli Wilson
3Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville MD
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Crystal McKnight
3Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville MD
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Jameson Travers
3Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville MD
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Carleen Klumpp-Thomas
3Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville MD
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Grace A. Smith
6Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD
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Stefania Pittaluga
6Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD
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Irina Maric
7Hematology Service, Department of Laboratory Medicine, National Institutes of Health Clinical Center, Bethesda MD
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Dickran Kazandjian
8Department of Medicine, University of Miami Health System, Miami FL
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Craig J. Thomas
1Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD
3Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville MD
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Ryan M. Young
1Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD
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  • For correspondence: youngrm@nih.gov
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Abstract

Oncogenic mutations within the RAS pathway are common in multiple myeloma (MM), an incurable malignancy of plasma cells. However, the mechanisms of pathogenic RAS signaling in this disease remain enigmatic and difficult to inhibit therapeutically. We employed an unbiased proteogenomic approach to dissect RAS signaling in MM by combining genome-wide CRISPR-Cas9 screening with quantitative mass spectrometry focused on RAS biology. We discovered that mutant isoforms of RAS organized a signaling complex with the amino acid transporter, SLC3A2, and MTOR on endolysosomes, which directly activated mTORC1 by co-opting amino acid sensing pathways. MM tumors with high expression of mTORC1-dependent genes were more aggressive and enriched in RAS mutations, and we detected interactions between RAS and MTOR in MM patient tumors harboring mutant RAS isoforms. Inhibition of RAS-dependent mTORC1 activity synergized with MEK and ERK inhibitors to quench pathogenic RAS signaling in MM cells. This study redefines the RAS pathway in MM and provides a mechanistic and rational basis to target this novel mode of RAS signaling.

Competing Interest Statement

The authors have declared no competing interest.

Footnotes

  • The authors declare no potential conflicts of interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Oncogenic RAS commandeers amino acid sensing machinery to aberrantly activate mTORC1 in multiple myeloma
Yandan Yang, Thomas Oellerich, Ping Chen, Arnold Bolomsky, Michele Ceribelli, Björn Häupl, George W. Wright, James D. Phelan, Da Wei Huang, James W. Lord, Callie K. Van Winkle, Xin Yu, Jan Wisnieski, James Q. Wang, Frances A. Tosto, Erin Beck, Kelli Wilson, Crystal McKnight, Jameson Travers, Carleen Klumpp-Thomas, Grace A. Smith, Stefania Pittaluga, Irina Maric, Dickran Kazandjian, Craig J. Thomas, Ryan M. Young
bioRxiv 2021.11.28.470260; doi: https://doi.org/10.1101/2021.11.28.470260
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Oncogenic RAS commandeers amino acid sensing machinery to aberrantly activate mTORC1 in multiple myeloma
Yandan Yang, Thomas Oellerich, Ping Chen, Arnold Bolomsky, Michele Ceribelli, Björn Häupl, George W. Wright, James D. Phelan, Da Wei Huang, James W. Lord, Callie K. Van Winkle, Xin Yu, Jan Wisnieski, James Q. Wang, Frances A. Tosto, Erin Beck, Kelli Wilson, Crystal McKnight, Jameson Travers, Carleen Klumpp-Thomas, Grace A. Smith, Stefania Pittaluga, Irina Maric, Dickran Kazandjian, Craig J. Thomas, Ryan M. Young
bioRxiv 2021.11.28.470260; doi: https://doi.org/10.1101/2021.11.28.470260

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