MLN4924 induces Noxa upregulation in acute myelogenous leukemia and synergizes with Bcl-2 inhibitors

K. L B Knorr, P. A. Schneider, X. W. Meng, H. Dai, B. D. Smith, A. D. Hess, J. E. Karp, Scott H Kaufmann

Research output: Contribution to journalArticle

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Abstract

MLN4924 (pevonedistat), an inhibitor of the Nedd8 activating enzyme (NAE), has exhibited promising clinical activity in acute myelogenous leukemia (AML). Here we demonstrate that MLN4924 induces apoptosis in AML cell lines and clinical samples via a mechanism distinct from those observed in other malignancies. Inactivation of E3 cullin ring ligases (CRLs) through NAE inhibition causes accumulation of the CRL substrate c-Myc, which transactivates the PMAIP1 gene encoding Noxa, leading to increased Noxa protein, Bax and Bak activation, and subsequent apoptotic changes. Importantly, c-Myc knockdown diminishes Noxa induction; and Noxa siRNA diminishes MLN4924-induced killing. Because Noxa also neutralizes Mcl-1, an anti-apoptotic Bcl-2 paralog often upregulated in resistant AML, further experiments have examined the effect of combining MLN4924 with BH3 mimetics that target other anti-apoptotic proteins. In combination with ABT-199 or ABT-263 (navitoclax), MLN4924 exerts a synergistic cytotoxic effect. Collectively, these results provide new insight into MLN4924-induced engagement of the apoptotic machinery that could help guide further exploration of MLN4924 for AML.

Original languageEnglish (US)
Pages (from-to)2133-2142
Number of pages10
JournalCell Death and Differentiation
Volume22
Issue number12
DOIs
StatePublished - Dec 1 2015

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Noxae
Acute Myeloid Leukemia
Up-Regulation
Cullin Proteins
Ligases
bcl-2 Homologous Antagonist-Killer Protein
bcl-2-Associated X Protein
Apoptosis Regulatory Proteins
Enzymes
((1S,2S,4R)-4-(4-((1S)-2,3-dihydro-1H-inden-1-ylamino)-7H-pyrrolo(2,3-d)pyrimidin-7-yl)-2-hydroxycyclopentyl)methyl sulphamate
Small Interfering RNA
Apoptosis
Cell Line

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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MLN4924 induces Noxa upregulation in acute myelogenous leukemia and synergizes with Bcl-2 inhibitors. / Knorr, K. L B; Schneider, P. A.; Meng, X. W.; Dai, H.; Smith, B. D.; Hess, A. D.; Karp, J. E.; Kaufmann, Scott H.

In: Cell Death and Differentiation, Vol. 22, No. 12, 01.12.2015, p. 2133-2142.

Research output: Contribution to journalArticle

Knorr, K. L B ; Schneider, P. A. ; Meng, X. W. ; Dai, H. ; Smith, B. D. ; Hess, A. D. ; Karp, J. E. ; Kaufmann, Scott H. / MLN4924 induces Noxa upregulation in acute myelogenous leukemia and synergizes with Bcl-2 inhibitors. In: Cell Death and Differentiation. 2015 ; Vol. 22, No. 12. pp. 2133-2142.
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