Bortezomib is significantly beneficial for de novo pediatric AML patients with low phosphorylation of the NF-κB subunit RelA

Anneke D. van Dijk, Fieke W. Hoff, Yihua Qiu, Robert B. Gerbing, Alan S. Gamis, Richard Aplenc, E. Anders Kolb, Todd A. Alonzo, Soheil Meshinchi, Gaye N. Jenkins, Eveline S.J.M. de Bont, Steven M. Kornblau, Terzah M. Horton

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Purpose: The addition of the proteasome inhibitor (PI) bortezomib to standard chemotherapy (ADE: cytarabine [Ara-C], daunorubicin, and etoposide) did not improve overall outcome of pediatric AML patients in the Children's Oncology Group AAML1031 phase 3 randomized clinical trial (AAML1031). Bortezomib prevents protein degradation, including RelA via the intracellular NF-kB pathway. In this study, we hypothesized that subgroups of pediatric AML patients benefitting from standard therapy plus bortezomib (ADEB) could be identified based on pre-treatment RelA expression and phosphorylation status. Experimental design: RelA-total and phosphorylation at serine 536 (RelA-pSer536) were measured in 483 patient samples using reverse phase protein array technology. Results: In ADEB-treated patients, low-RelA-pSer536 was favorably prognostic when compared to high-RelA-pSer536 (3-yr overall survival (OS): 81% vs. 68%, p = 0.032; relapse risk (RR): 30% vs. 49%, p = 0.004). Among low-RelA-pSer536 patients, RR significantly decreased with ADEB compared to ADE (RR: 30% vs. 44%, p = 0.035). Correlation between RelA-pSer536 and 295 other assayed proteins identified a strong correlation with HSF1-pSer326, another protein previously identified as modifying ADEB response. The combination of low-RelA-pSer536 and low-HSF1-pSer326 was a significant predictor of ADEB response (3-yr OS: 86% vs. 67%, p = 0.013). Conclusion and clinical relevance: Bortezomib may improve clinical outcome in a subgroup of AML patients identified by low-RelA-pSer536 and low-HSF1-pSer326.

Original languageEnglish
Article number2100072
JournalProteomics - Clinical Applications
Volume16
Issue number2
DOIs
StatePublished - Mar 2022
Externally publishedYes

Keywords

  • B ortezomib
  • RPPA
  • leukemia
  • pediatric
  • proteomics

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