RPPA-Profiling Identifies Patients with Low Phosphorylation Levels of HSF1 at Serine 326 As Potential Candidate for Bortezomib Treatment in Addition to Standard Therapy in Pediatric Acute Myeloid Leukemia

▪ Background: Heat shock factor 1 (HSF1) is a key-component of the heat shock response and plays a major role in cancer biology. The heat shock response is a highly conserved mechanism that is important for cell survival under stressful conditions. It facilitates normal protein folding and guards th...

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Veröffentlicht in:Blood 2018-11, Vol.132 (Supplement 1), p.293-293
Hauptverfasser: Hoff, Fieke W, Hu, Wendy, Qiu, Yihua, Gamis, Alan S, Aplenc, Richard, Kolb, E. Anders, Alonzo, Todd A, Qutub, Amina A, de Bont, Eveline S., Bruggeman, Sophia W.M., Kornblau, Steven M., Horton, Terzah M.
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Sprache:eng
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Zusammenfassung:▪ Background: Heat shock factor 1 (HSF1) is a key-component of the heat shock response and plays a major role in cancer biology. The heat shock response is a highly conserved mechanism that is important for cell survival under stressful conditions. It facilitates normal protein folding and guards the proteome from misfolding and aggregation. Bortezomib (BTZ) is a reversible proteasome inhibitor and was recently tested in a phase 3 clinical trial for patients with de novo pediatric acute myeloid leukemia (pedi-AML). This trial compared standard therapy (cytarabine/daunorubicin/etoposide (ADE)) to ADE plus BTZ (ADE+B). As HSF1 and BTZ act in opposing circumstances, our goal was to globally assess the phosphorylation of HSF1 at serine 326 (HSF1.pS326) and to determine if baseline HSF1.pS326 was prognostic of clinical response to ADE+B and if we could identify a subset of patients that benefitted from ADE+B. Methods: Reverse phase protein array (RPPA) probed with 222 total antibodies and 69 specific post-translationally modified proteins was used to determine the protein expression levels in 505 bulk leukemic pedi-AML samples compared to 20 CD34+ samples from healthy pediatric donors. Patients participated in the Children's Oncology Group (COG) AAML1031 Phase 3 clinical trial that compared ADE to ADE+B. Survival curves were generated using the Kaplan-Meier method. Results: HSF1.pS326 protein expression levels in the pedi-AML patient samples. Based on the HSF1.pS326 expression levels, patients were classified into two clusters; high HSF1 326 (n = 216) and low HSF1.326 (n = 289). The median of the normal CD34+ samples was used as cut-off point. Expression of HSF1.pS326 was not prognostic for outcome in patients treated with ADE (event-free survival (EFS), p = 0.51) (Fig. 1A). In patients that were treated with ADE+B however, HSF1.pS326 levels were highly prognostic, with low HSF1.pS326 associated with a better EFS (p = 0.009) (Fig. 1B). Patients with high HSF1.pS326 did not benefit from BTZ addition (EFS, p = 0.77) (Fig. 1C), whereas patients with low HSF1.pS326 levels significantly improved (EFS, p = 0.004) (Fig. 1D). Between the two patient clusters, the NPM1 mutation state was higher in patients with high HSF1.pS326 levels (p = 0.042), and the CEBPA mutation state was higher in patients with low HSF1.pS326 (p = 0.011). No other patient or disease characteristics were different between the two clusters. To functionally validate our findings, we overexpressed w
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2018-99-110730