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RAL GTPases mediate multiple myeloma cell survival and are activated independently of oncogenic RAS.

Authors
  • Seibold, Marcel1
  • Stühmer, Thorsten2
  • Kremer, Nadine2
  • Mottok, Anja3
  • Scholz, Claus-Jürgen4
  • Schlosser, Andreas5
  • Leich, Ellen6
  • Holzgrabe, Ulrike7
  • Brünnert, Daniela2
  • Barrio, Santiago8
  • Kortüm, K Martin1
  • Solimando, Antonio G1
  • Chatterjee, Manik2
  • Einsele, Hermann1
  • Rosenwald, Andreas6
  • Bargou, Ralf C2
  • Steinbrunn, Torsten9
  • 1 Department of Medicine II, University Hospital of Würzburg, Germany. , (Germany)
  • 2 Comprehensive Cancer Center Mainfranken, University Hospital of Würzburg, Germany. , (Germany)
  • 3 Institute of Human Genetics, University of Ulm, Germany. , (Germany)
  • 4 Core Unit Systems Medicine, University of Würzburg, Germany. , (Germany)
  • 5 Rudolf Virchow Center for Experimental Biomedicine, University of Würzburg, Germany. , (Germany)
  • 6 Institute of Pathology, University of Würzburg, Germany. , (Germany)
  • 7 Institute of Pharmacy and Food Chemistry, University of Würzburg, Germany. , (Germany)
  • 8 Hematology Department, Hospital 12 de Octubre, Complutense University, Madrid, Spain. , (Spain)
  • 9 Department of Medicine II, University Hospital of Würzburg, Germany; [email protected] , (Germany)
Type
Published Article
Journal
Haematologica
Publisher
Ferrata Storti Foundation
Publication Date
Oct 10, 2019
Identifiers
DOI: 10.3324/haematol.2019.223024
PMID: 31601693
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Oncogenic RAS provides crucial survival signaling for up to half of multiple myeloma cases, but has so far remained a clinically undruggable target. RAL is a member of the RAS superfamily of small GTPases and is considered to be a potential mediator of oncogenic RAS signaling. In primary multiple myeloma, we found RAL to be overexpressed in the vast majority of samples when compared with pre-malignant monoclonal gammopathy of undetermined significance or normal plasma cells. We analyzed the functional effects of RAL abrogation in myeloma cell lines and found that RAL is a critical mediator of survival. RNAi-mediated knockdown of RAL resulted in rapid induction of tumor cell death, an effect which was independent from signaling via mitogen-activated protein kinase, but appears to be partially dependent on Akt activity. Notably, RAL activation was not correlated with the presence of activating RAS mutations and remained unaffected by knockdown of oncogenic RAS. Furthermore, transcriptome analysis yielded distinct RNA expression signatures after knockdown of either RAS or RAL. Combining RAL depletion with clinically relevant anti-myeloma agents led to enhanced rates of cell death. Our data demonstrate that RAL promotes multiple myeloma cell survival independently of oncogenic RAS and, thus, this pathway represents a potential therapeutic target in its own right. Copyright © 2019, Ferrata Storti Foundation.

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