Written by | Miao Xinfang, editor-in-charge of | Zhou Yebin
Although the long-term survival rate of acute myeloid leukemia (AML) in children has improved significantly, it is still poor compared with pediatric acute lymphoblastic leukemia (ALL). 90% of children achieve complete remission after induction therapy, but 50% still relapse, and only one-third are cured after recurrence. Therefore, pediatric acute myeloid leukemia requires new treatments to improve prognosis.
Bortezomib (BTZ) is a proteasome inhibitor that is effective against multiple myeloma and mantle cell lymphoma. In clinical trials of adult AML, BTZ can be used in combination with AML standard chemotherapy. BTZ causes cell death by interfering with protein homeostasis, causing toxic buildup of misfolded proteins in cells or proteome stress. But BTZ treatment also allows cells to activate adaptation mechanisms, including heat shock reactions, that allow cells to survive protein toxic pressures. The heat shock reaction is mediated by heat shock reaction factor 1 (abbreviated HSF1) and activated by HSF1-pSer326. High levels of HSF1 have been associated with poor prognosis for solid cancers such as breast, lung, and bowel cancer, but the role of HSF1 in children's AML has not been established.
On February 25, 2021, several joint research teams from the Netherlands and the United States published an article on Blood titled Heat shock factor 1 (HSF1-pSer326) predicts response to bortezomib-containing chemotherapy in pediatric AML: a COG report. A Phase III clinical trial of the pediatric oncology group (abbreviated COG) was described. By comparing 483 children with AML receiving standard chemotherapy with BTZ combined with standard chemotherapy, total HSF1 and HSF1-pSer326 were measured, and patients with higher HSF1-pSer326 were found to be more resistant to BTZ. Therefore, HSF1 and HSF1-pSer326 expressions can be used to identify patients who are beneficial to BTZ combination chemotherapy.
First, the researchers analyzed the protein expression of HSF1-total and HSF1-pSer326 in 483 children with AML and 20 healthy children and 10 healthy adults. In children's AML cells (n=483), both HSF1-total and HSF1-pSer326 were significantly lower than cells in healthy donors (n=30).
Protein expression levels of HSF1-total(A) and HSF1-pSer326(B) in 483 child AML cells and 30 healthy donor cells.
Second, among children treated with BTZ, those with low expression of HSF1-pSer326 had a good prognosis. The researchers first analyzed HSF1-total and HSF1-pSer326 protein expressions in all children, both receiving or not receiving BZT treatment, and found that they did not predict overall survival (OS) and event-free survival (EFS) in children. However, when the expression of the HSF1-pSer326 protein was assessed in the BTZ treatment group alone, the OS and EFS of children with moderate or high HSF1-pSer326 expression decreased gradually, associated with a corresponding increase in recurrence rates.
Children receiving standard therapy had low HSF1-pSer326, (A) OS at moderate and high expression, (B) EFS, (C) RR; children treated with BTZ had low HSF1-pSer326, (A)OS, (B) EFS, (C) RR at high expression; the red line represented the low expression of HSF1-pSer326, the blue line represented the moderate expression of HSF1-pSer326, and the green line represented the high expression of HSF1-pSer326.
HSF1-pSer326 low-expression (A)OS, (B) EFS, (C) RR in children receiving standard therapy or BTZ; HSF1-pSer326 high-expression (A)OS, (B) EFS, (C) RR in children receiving standard therapy or BTZ; red lines representing receiving standard of care and blue lines representing treatment with BTZ.
In addition, the researchers found that HSF1-pSer326 can be used as an independent factor predicting survival in patients treated with BTZ, and in vitro studies confirmed that the serine 326 phosphorylation site is critical to the sensitivity of BTZ.
The researchers also found that the effect of chemotherapy on HSF1-pSer326 expression depended on the relative abundance of HSF1-pSer326. Previously, in myeloma, an increase in HSF1-pSer326 expression after receiving BTZ therapy has been confirmed. In this experiment, by comparing the expression of HSF1-pSer326 in the blood before and after receiving chemotherapy (10 and 24 hours), the researchers found that HSF1-pSer326 expression in patients with low HSF1-pSer326 before treatment increased after chemotherapy, while HSF1-pSer326 expression in patients with high HSF1-pSer326 before treatment did not change after chemotherapy.
Changes in HSF1-pSer326 expression after receiving chemotherapy. Blue was for patients with low HSF1-pSer326 before chemotherapy, and red was for patients with high HSF1-pSer326 before chemotherapy.
In summary, although BTZ in the Phase III clinical trial of COG did not show an advantage over chemotherapy alone, so the inclusion of BTZ in the standard treatment of AML in children was not recommended, through subgroup analysis, the researchers successfully found a subgroup that benefited from the BTZ experiment: children with low HSF1-pSer326 expression before treatment. Decreased expression of HSF1-pSer326 is associated with an increased response to BTZ-containing chemotherapy in children's AML, suggesting that abundance of HSF1-pSer326 may be important in chemotherapy options with BTZ.
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