RNA interference screening identifies lenalidomide sensitizers in multiple myeloma, including RSK2

Yuan Xiao Zhu, Hongwei Yin, Laura A. Bruins, Chang Xin Shi, Patrick Jedlowski, Meraj Aziz, Chris Sereduk, Klaus Martin Kortuem, Jessica E. Schmidt, Mia Champion, Esteban D Braggio, Alexander Keith Stewart

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

To identify molecular targets that modify sensitivity to lenalidomide, we measured proliferation in multiple myeloma (MM) cells transfected with 27 968 small interfering RNAs in the presence of increasing concentrations of drug and identified 63 genes that enhance activity of lenalidomide upon silencing. Ribosomal protein S6 kinase (RPS6KA3 or RSK2) was the most potent sensitizer. Other notable gene targets included 5 RAB family members, 3 potassium channel proteins, and 2 peroxisome family members. Single genes of interest included I-κ-B kinase-α (CHUK), and a phosphorylation dependent transcription factor (CREB1), which associate with RSK2 to regulate several signaling pathways. RSK2 knockdown induced cytotoxicity across a panel of MM cell lines and consistently increased sensitivity to lenalidomide. Accordingly, 3 small molecular inhibitors of RSK2 demonstrated synergy with lenalidomide cytotoxicity in MM cells even in the presence of stromal contact. Both RSK2 knockdown and smallmolecule inhibition downregulate interferon regulatory factor 4 and MYC, and provides an explanation for the synergy between lenalidomide and RSK2 inhibition. Interestingly, RSK2 inhibition also sensitized MM cells to bortezomib, melphalan, and dexamethasone, but did not downregulate Ikaros or influence lenalidomide-mediated downregulation of tumor necrosis factor-α or increase lenalidomide-induced IL-2 upregulation. In summary, inhibition of RSK2 may prove a broadly useful adjunct to MM therapy.

Original languageEnglish (US)
Pages (from-to)483-491
Number of pages9
JournalBlood
Volume125
Issue number3
DOIs
StatePublished - Jan 15 2015

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RNA Interference
Multiple Myeloma
Screening
RNA
Down-Regulation
Genes
Cytotoxicity
I-kappa B Kinase
Ribosomal Protein S6 Kinases
Phosphorylation
Melphalan
Peroxisomes
Potassium Channels
lenalidomide
Dexamethasone
Small Interfering RNA
Interleukin-2
Transcription Factors
Up-Regulation
Tumor Necrosis Factor-alpha

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

RNA interference screening identifies lenalidomide sensitizers in multiple myeloma, including RSK2. / Zhu, Yuan Xiao; Yin, Hongwei; Bruins, Laura A.; Shi, Chang Xin; Jedlowski, Patrick; Aziz, Meraj; Sereduk, Chris; Kortuem, Klaus Martin; Schmidt, Jessica E.; Champion, Mia; Braggio, Esteban D; Stewart, Alexander Keith.

In: Blood, Vol. 125, No. 3, 15.01.2015, p. 483-491.

Research output: Contribution to journalArticle

Zhu, YX, Yin, H, Bruins, LA, Shi, CX, Jedlowski, P, Aziz, M, Sereduk, C, Kortuem, KM, Schmidt, JE, Champion, M, Braggio, ED & Stewart, AK 2015, 'RNA interference screening identifies lenalidomide sensitizers in multiple myeloma, including RSK2', Blood, vol. 125, no. 3, pp. 483-491. https://doi.org/10.1182/blood-2014-05-577130
Zhu, Yuan Xiao ; Yin, Hongwei ; Bruins, Laura A. ; Shi, Chang Xin ; Jedlowski, Patrick ; Aziz, Meraj ; Sereduk, Chris ; Kortuem, Klaus Martin ; Schmidt, Jessica E. ; Champion, Mia ; Braggio, Esteban D ; Stewart, Alexander Keith. / RNA interference screening identifies lenalidomide sensitizers in multiple myeloma, including RSK2. In: Blood. 2015 ; Vol. 125, No. 3. pp. 483-491.
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