First name
Eveline
Middle name
S J M
Last name
De Bont

Title

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

Year of Publication

2021

Number of Pages

e2100072

Date Published

2021 Nov 01

ISSN Number

1862-8354

Abstract

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-pSer ) levels were measured in 483 patient samples using reverse phase protein array technology. In ADEB-treated patients, low-RelA-pSer was favorably prognostic when compared to high-RelA-pSer (3-yr overall survival (OS): 81% vs. 68%, p = 0.032; relapse risk (RR): 30% vs. 49%, p = 0.004). RR in low-RelA-pSer patients significantly decreased in ADEB compared to ADE (RR: 30% vs. 44%, p = 0.035). Correlation between RelA-pSer and 295 other assayed proteins identified a strong correlation with HSF1-pSer , another protein previously identified as modifying ADEB response. The combination of low-RelA-pSer and low-HSF1-pSer 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-pSer and low-HSF1-pSer . This article is protected by copyright. All rights reserved.

DOI

10.1002/prca.202100072

Alternate Title

Proteomics Clin Appl

PMID

34719869

Title

Clinical relevance of proteomic profiling in de novo pediatric acute myeloid leukemia: a Children's Oncology Group study.

Year of Publication

2022

Date Published

2022 Jan 13

ISSN Number

1592-8721

Abstract

<p>Pediatric acute myeloid leukemia (AML) remains a fatal disease for at least 30% of patients, stressing the need for improved therapies and better risk stratification. As proteins are the unifying feature of (epi)genetic and environmental alterations, and are often targeted by novel chemotherapeutic agents, we studied the proteomic landscape of pediatric AML. Protein expression and activation levels were measured in 500 bulk leukemic patient samples and 30 control CD34+ samples, using the reverse phase protein arrays with 296 strictly validated antibodies. The multi-step "MetaGalaxy" analysis methodology was applied and identified nine protein expression signatures (PrSIG), based on strong recurrent protein expression patterns. PrSIGs were associated with cytogenetics and mutational state, and with both favorable or unfavorable prognosis. Analysis based on treatment (i.e., ADE vs. ADE plus bortezomib (ADEB)) identified three PrSIGs that did better with ADEB vs. ADE. When PrSIGs were studied in the context of genetic subgroups, PrSIGs were independently prognostic after multivariate analysis, suggesting a potential value for proteomics in combination with current classification systems. Proteins with universally increased (n=7) or decreased (n=17) expression were observed across PrSIGs. Expression of certain proteins significantly differentially expressed from normal could be identified, forming a hypothetical platform for personalized medicine.</p>

DOI

10.3324/haematol.2021.279672

Alternate Title

Haematologica

PMID

35021602

Title

Heat Shock Factor 1 (HSF1-pSer326) Predicts Response to Bortezomib-Containing Chemotherapy in Pediatric AML: A COG Study.

Year of Publication

2020

Date Published

2020 Sep 21

ISSN Number

1528-0020

Abstract

<p>Bortezomib (BTZ) was recently evaluated in a randomized Phase 3 clinical trial which compared standard chemotherapy (cytarabine, daunorubicin, etoposide; ADE) to standard therapy with BTZ (ADEB) for de novo pediatric acute myeloid leukemia. While the study concluded that BTZ did not improve outcome overall, we examined patient subgroups benefitting from BTZ-containing chemotherapy using proteomic analyses. The proteasome inhibitor BTZ disrupts protein homeostasis and activates cytoprotective heat shock responses. We measured total heat shock factor 1 (HSF1) and phosphorylated HSF1 (HSF1-pSer326) in leukemic cells from 483 pediatric patients using Reverse Phase Protein Arrays. HSF1-pSer326 phosphorylation was significantly lower in pediatric AML compared to CD34+ non-malignant cells. We identified a strong correlation between HSF1-pSer326 expression and BTZ sensitivity. BTZ significantly improved outcome of patients with low-HSF1-pSer326 with a 5-year event-free survival of 44% (ADE) vs. 67% for low-HSF1-pSer326 treated with ADEB (P=0.019). To determine the effect of HSF1 expression on BTZ potency in vitro, cell viability with HSF1 gene variants that mimicked phosphorylated (S326A) and non-phosphorylated (S326E) HSF1-pSer326 were examined. Those with increased HSF1 phosphorylation showed clear resistance to BTZ vs. those with wild type or reduced HSF1-phosphorylation. We hypothesize that HSF1-pSer326 expression could identify patients that benefit from BTZ-containing chemotherapy.</p>

DOI

10.1182/blood.2020005208

Alternate Title

Blood

PMID

32959058

Title

Collaborative Efforts Driving Progress in Pediatric Acute Myeloid Leukemia.

Year of Publication

2015

Number of Pages

2949-62

Date Published

2015 Sep 20

ISSN Number

1527-7755

Abstract

<p>Diagnosis, treatment, response monitoring, and outcome of pediatric acute myeloid leukemia (AML) have made enormous progress during the past decades. Because AML is a rare type of childhood cancer, with an incidence of approximately seven occurrences per 1 million children annually, national and international collaborative efforts have evolved. This overview describes these efforts and includes a summary of the history and contributions of each of the main collaborative pediatric AML groups worldwide. The focus is on translational and clinical research, which includes past, current, and future clinical trials. Separate sections concern acute promyelocytic leukemia, myeloid leukemia of Down syndrome, and relapsed AML. A plethora of novel antileukemic agents that have emerged, including new classes of drugs, are summarized as well. Finally, an important aspect of the treatment of pediatric AML--supportive care--and late effects are discussed. The future is bright, with a wide range of emerging innovative therapies and with more and more international collaboration that ultimately aim to cure all children with AML, with fewer adverse effects and without late effects.</p>

DOI

10.1200/JCO.2015.62.8289

Alternate Title

J. Clin. Oncol.

PMID

26304895

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