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

van Dijk AD, Hoff FW, Qiu Y, Gerbing RB, Gamis AS, Aplenc R, Kolb EA, Alonzo TA, Meshinchi S, Jenkins GN, de Bont ESJM, Kornblau SM, Horton TM. Bortezomib is significantly beneficial for de novo pediatric AML patients with low phosphorylation of the NF-κB subunit RelA. Proteomics Clin Appl. 2022 Mar;16(2):e2100072. doi: 10.1002/prca.202100072. Epub 2021 Nov 17. PubMed PMID: 34719869; PubMed Central PMCID: PMC9041833.

The addition of the proteasome inhibitor (PI) bortezomib to standard chemotherapy (ADE: cytarabine [Ara-C], daunorubicin and etoposide,) did not improve overall outcome 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. RelA-total and phosphorylation at serine 536 (RelA-pSer536) levels were measured in 483 patient samples using reverse phase protein array technology. 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). RR in low-RelA-pSer536 patients significantly decreased in 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). Thus, bortezomib may improve clinical outcome in a subgroup of AML patients identified by low-RelA-pSer536 and low-HSF1-pSer326.