PMA exerts anti-leukemia effect in Ph⁺ ALL through activating PKC δ and its down-stream molecules

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph⁺ ALL) is a subtype of precursor B ALL in genetics and is recognized as a subclass with poor prognosis. Tyrosine kinase inhibitors (TKIs) greatly improve the prognosis of Ph⁺ ALL patients. However, the long-term survival rate is still low (with a 3-year survival rate only 55%). Hence, it is urgent to explore new therapies to improve prognosis for Ph⁺ ALL patients. Protein kinase C (PKC) is proven to be a tumor suppressor in recent years. Activation of PKC by its novel agonist PMA reverts the malignancy of many hematological diseases. However, the effect of PMA on Ph⁺ ALL is unclear.

We investigated the biological effects of PMA on Ph⁺ ALL cells and the potential mechanism in this study. In this study, the SUP-B15 and BP190 cell lines were subjected to PMA treatment. Cell proliferation, cycle distribution, apoptosis, protein expression levels, and gene expression changes were assessed using CCK-8 assay, flow cytometry, Western blot analysis, DAPI staining, and quantitative real-time PCR. Additionally, bone marrow mononuclear cells were isolated for further investigation, and RNA sequencing was conducted on SUP-B15 cells. Furthermore, the mouse model was established to evaluate the in vivo biological effects of PMA.

We found that PMA could promote apoptosis, inhibit proliferation and promote differentiation of human Ph⁺ ALL cells. More importantly, we demonstrated for the first time that these effects caused by PMA were related to the activation of PKC δ and its down-stream molecules, such as p-ERK, p21 and so on.

PMA exerts an anti-leukemia effect in Ph⁺ ALL by activating PKC δ and its downstream molecules, thereby demonstrating its potential as a therapeutic agent for Ph⁺ ALL.