Inhibition of the aryl hydrocarbon receptor/polyamine biosynthesis axis suppresses multiple myeloma

Anna Bianchi-Smiraglia, Archis Bagati, Emily E. Fink, Hayley C. Affronti, Brittany C. Lipchick, Sudha Moparthy, Mark D. Long, Spencer R. Rosario, Shivana M. Lightman, Kalyana Moparthy, David W. Wolff, Dong Hyun Yun, Zhannan Han, Anthony Polechetti, Matthew V. Roll, Ilya I. Gitlin, Katerina I. Leonova, Aryn M. Rowsam, Eugene S. Kandel, Andrei V. GudkovPeter Leif Bergsagel, Kelvin P. Lee, Dominic J. Smiraglia, Mikhail A. Nikiforov

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Polyamine inhibition for cancer therapy is, conceptually, an attractive approach but has yet to meet success in the clinical setting. The aryl hydrocarbon receptor (AHR) is the central transcriptional regulator of the xenobiotic response. Our study revealed that AHR also positively regulates intracellular polyamine production via direct transcriptional activation of 2 genes, ODC1 and AZIN1, which are involved in polyamine biosynthesis and control, respectively. In patients with multiple myeloma (MM), AHR levels were inversely correlated with survival, suggesting that AHR inhibition may be beneficial for the treatment of this disease. We identified clofazimine (CLF), an FDA-approved anti-leprosy drug, as a potent AHR antagonist and a suppressor of polyamine biosynthesis. Experiments in a transgenic model of MM (Vk*Myc mice) and in immunocompromised mice bearing MM cell xenografts revealed high efficacy of CLF comparable to that of bortezomib, a first-in-class proteasome inhibitor used for the treatment of MM. This study identifies a previously unrecognized regulatory axis between AHR and polyamine metabolism and reveals CLF as an inhibitor of AHR and a potentially clinically relevant anti-MM agent.

Original languageEnglish (US)
Pages (from-to)4682-4696
Number of pages15
JournalJournal of Clinical Investigation
Volume128
Issue number10
DOIs
StatePublished - Oct 1 2018

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Aryl Hydrocarbon Receptors
Polyamines
Multiple Myeloma
Clofazimine
Proteasome Inhibitors
Xenobiotics
Leprosy
Heterografts
Transcriptional Activation
Therapeutics
Survival
Pharmaceutical Preparations
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Bianchi-Smiraglia, A., Bagati, A., Fink, E. E., Affronti, H. C., Lipchick, B. C., Moparthy, S., ... Nikiforov, M. A. (2018). Inhibition of the aryl hydrocarbon receptor/polyamine biosynthesis axis suppresses multiple myeloma. Journal of Clinical Investigation, 128(10), 4682-4696. https://doi.org/10.1172/JCI70712

Inhibition of the aryl hydrocarbon receptor/polyamine biosynthesis axis suppresses multiple myeloma. / Bianchi-Smiraglia, Anna; Bagati, Archis; Fink, Emily E.; Affronti, Hayley C.; Lipchick, Brittany C.; Moparthy, Sudha; Long, Mark D.; Rosario, Spencer R.; Lightman, Shivana M.; Moparthy, Kalyana; Wolff, David W.; Yun, Dong Hyun; Han, Zhannan; Polechetti, Anthony; Roll, Matthew V.; Gitlin, Ilya I.; Leonova, Katerina I.; Rowsam, Aryn M.; Kandel, Eugene S.; Gudkov, Andrei V.; Bergsagel, Peter Leif; Lee, Kelvin P.; Smiraglia, Dominic J.; Nikiforov, Mikhail A.

In: Journal of Clinical Investigation, Vol. 128, No. 10, 01.10.2018, p. 4682-4696.

Research output: Contribution to journalArticle

Bianchi-Smiraglia, A, Bagati, A, Fink, EE, Affronti, HC, Lipchick, BC, Moparthy, S, Long, MD, Rosario, SR, Lightman, SM, Moparthy, K, Wolff, DW, Yun, DH, Han, Z, Polechetti, A, Roll, MV, Gitlin, II, Leonova, KI, Rowsam, AM, Kandel, ES, Gudkov, AV, Bergsagel, PL, Lee, KP, Smiraglia, DJ & Nikiforov, MA 2018, 'Inhibition of the aryl hydrocarbon receptor/polyamine biosynthesis axis suppresses multiple myeloma', Journal of Clinical Investigation, vol. 128, no. 10, pp. 4682-4696. https://doi.org/10.1172/JCI70712
Bianchi-Smiraglia A, Bagati A, Fink EE, Affronti HC, Lipchick BC, Moparthy S et al. Inhibition of the aryl hydrocarbon receptor/polyamine biosynthesis axis suppresses multiple myeloma. Journal of Clinical Investigation. 2018 Oct 1;128(10):4682-4696. https://doi.org/10.1172/JCI70712
Bianchi-Smiraglia, Anna ; Bagati, Archis ; Fink, Emily E. ; Affronti, Hayley C. ; Lipchick, Brittany C. ; Moparthy, Sudha ; Long, Mark D. ; Rosario, Spencer R. ; Lightman, Shivana M. ; Moparthy, Kalyana ; Wolff, David W. ; Yun, Dong Hyun ; Han, Zhannan ; Polechetti, Anthony ; Roll, Matthew V. ; Gitlin, Ilya I. ; Leonova, Katerina I. ; Rowsam, Aryn M. ; Kandel, Eugene S. ; Gudkov, Andrei V. ; Bergsagel, Peter Leif ; Lee, Kelvin P. ; Smiraglia, Dominic J. ; Nikiforov, Mikhail A. / Inhibition of the aryl hydrocarbon receptor/polyamine biosynthesis axis suppresses multiple myeloma. In: Journal of Clinical Investigation. 2018 ; Vol. 128, No. 10. pp. 4682-4696.
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AU - Bianchi-Smiraglia, Anna

AU - Bagati, Archis

AU - Fink, Emily E.

AU - Affronti, Hayley C.

AU - Lipchick, Brittany C.

AU - Moparthy, Sudha

AU - Long, Mark D.

AU - Rosario, Spencer R.

AU - Lightman, Shivana M.

AU - Moparthy, Kalyana

AU - Wolff, David W.

AU - Yun, Dong Hyun

AU - Han, Zhannan

AU - Polechetti, Anthony

AU - Roll, Matthew V.

AU - Gitlin, Ilya I.

AU - Leonova, Katerina I.

AU - Rowsam, Aryn M.

AU - Kandel, Eugene S.

AU - Gudkov, Andrei V.

AU - Bergsagel, Peter Leif

AU - Lee, Kelvin P.

AU - Smiraglia, Dominic J.

AU - Nikiforov, Mikhail A.

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N2 - Polyamine inhibition for cancer therapy is, conceptually, an attractive approach but has yet to meet success in the clinical setting. The aryl hydrocarbon receptor (AHR) is the central transcriptional regulator of the xenobiotic response. Our study revealed that AHR also positively regulates intracellular polyamine production via direct transcriptional activation of 2 genes, ODC1 and AZIN1, which are involved in polyamine biosynthesis and control, respectively. In patients with multiple myeloma (MM), AHR levels were inversely correlated with survival, suggesting that AHR inhibition may be beneficial for the treatment of this disease. We identified clofazimine (CLF), an FDA-approved anti-leprosy drug, as a potent AHR antagonist and a suppressor of polyamine biosynthesis. Experiments in a transgenic model of MM (Vk*Myc mice) and in immunocompromised mice bearing MM cell xenografts revealed high efficacy of CLF comparable to that of bortezomib, a first-in-class proteasome inhibitor used for the treatment of MM. This study identifies a previously unrecognized regulatory axis between AHR and polyamine metabolism and reveals CLF as an inhibitor of AHR and a potentially clinically relevant anti-MM agent.

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