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

Randomized Controlled Trial

. 2022 Mar;16(2):e2100072.

doi: 10.1002/prca.202100072. Epub 2021 Nov 17.

Fieke W Hoff 1 2, Yihua Qiu 3, Robert B Gerbing 4, Alan S Gamis 5, Richard Aplenc 6, E Anders Kolb 7, Todd A Alonzo 8, Soheil Meshinchi 9, Gaye N Jenkins 10, Eveline S J M de Bont 1, Steven M Kornblau 3, Terzah M Horton 10

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Randomized Controlled Trial

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

Anneke D van Dijk et al. Proteomics Clin Appl. 2022 Mar.

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 .

Keywords: B ortezomib; RPPA; leukemia; pediatric; proteomics.

© 2021 Wiley-VCH GmbH.

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Conflict of interest statement

Competing interests

TMH receives research funding from Takeda Pharmaceuticals.

Figures

Figure 1.

Figure 1.. Kaplan-Meier survival analysis for low and high-RelA-pSer536.

A) OS, B) EFS and C) RR for low-RelA-pSer536 patients treated with ADE or ADES (grey dashed line) or ADEB (grey solid line), vs. high-RelA-Ser536 patients treated with ADE or ADES (black dashed line) or ADEB (black solid line).

Figure 2.

Figure 2.. Waterfall plot and network analysis of correlated proteins with RelA-pSer536.

A) Waterfall plot showing the 28 significantly correlated proteins with RelA-pSer536 (r ≥ 0.25, or r ≤ −0.25). * Denotes antibodies directed against PTM-sites. B) STRING networks analysis for the 24 proteins that correlated with both RelA-pSer536 and HSF1-pSer326. Only interactions with either RELA or HSF1 are shown.

Figure 3.

Figure 3.. Kaplan-Meier survival analysis for RelA-pSer536 and HSF1-pSer326 combined in ADEB-treated patients.

A) OS, B) EFS, and C) RR for patients stratified based on their RelA-pSer536 and HSF1-pSer326 expression levels. Solid grey: low-RelA-pSer536, low-HSF1-pSer326; dashed grey: low-RelA-pSer536, high-HSF1-pSer326; solid black: high-RelA-pSer536, low-HSF1-pSer326; dashed black: high-RelA-pSer536, high-HSF1-pSer326.

Figure 4.

Figure 4.. Schematic summary of RelA-pSer536 dependence in bortezomib treatment.

A) Patients were split based on pre-treatment RelA-pSer536 expression levels into low (blue) and high (red). B) Expression increases in low- RelA-pSer536 patients after treatment with chemotherapy (purple), but does not reach the same levels as found in the high- RelA-pSer536. In high- RelA-pSer536 patients, no increase in RelA-pSer536 was seen. C) Solid line represents baseline state of the leukemia cells with a tendency toward cell proliferation. After chemotherapy, this balances over to more apoptosis. We hypothesize that RelA-pSer536 plays a role in stress response caused by chemotherapy which is speculatively blocked by PI therapy, and that low- RelA-pSer536 patients are more dependent on this response. Size of the black arrow represents the increase in apoptosis. D) Increased cell stress result in cell death and cell death eventually leads to patient survival. Survival of low-RelA-pS536 increases after treatment with ADEB (solid line) vs. ADE (dashed line).

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