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

TitleHeat Shock Factor 1 (HSF1-pSer326) Predicts Response to Bortezomib-Containing Chemotherapy in Pediatric AML: A COG Study.
Publication TypeJournal Article
Year of Publication2020
AuthorsHoff FW, van Dijk AD, Qiu YHua, Ruvolo PP, Gerbing RB, Leonti AR, Jenkins GN, Gamis AS, Aplenc R, E Kolb A, Alonzo T, Meshinchi S, De Bont E, Bruggeman SWm, Kornblau SM, Horton TM
JournalBlood
Date Published2020 Sep 21
ISSN1528-0020
Abstract

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.

DOI10.1182/blood.2020005208
Alternate JournalBlood
PubMed ID32959058