Heat shock factor 1 (HSF1-pSer³²⁶) predicts response to bortezomib-containing chemotherapy in pediatric AML: a COG report

Bortezomib (BTZ) was recently evaluated in a randomized phase 3 clinical trial by the Children's Oncology Group (COG) that compared standard chemotherapy (cytarabine, daunorubicin, and etoposide [ADE]) vs standard therapy with BTZ (ADEB) for de novo pediatric acute myeloid leukemia (AML). Although the study concluded that BTZ did not improve outcome overall, we examined patient subgroups benefiting from BTZ-containing chemotherapy using proteomic analyses. The proteasome inhibitor BTZ disrupts protein homeostasis and activates cytoprotective heat shock responses. Total heat shock factor 1 (HSF1) and phosphorylated HSF1 (HSF1-pSer³²⁶) were measured in leukemic cells from 483 pediatric patients using reverse phase protein arrays. HSF1-pSer³²⁶ phosphorylation was significantly lower in pediatric AML compared with CD34⁺ nonmalignant 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 = .019). To determine the effect of HSF1 expression on BTZ potency in vitro, cell viability with HSF1 gene variants that mimicked phosphorylated (S326A) and nonphosphorylated (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 who benefit from BTZ-containing chemotherapy. Key Points: • Low-HSF1-pSer³²⁶ is a favorable prognostic protein in patients treated with BTZ-containing chemotherapy. • Addition of BTZ to standard chemotherapy significantly improves outcome in low-HSF1-pSer³²⁶ pediatric patients with AML.