Merit of the paper "PP2A inhibition sensitize cancer stem cells to ABL tyrosine kinase inhibition in BCR-ABL human leukemia" authored by Lai et al. [Science Translational Medicine (2019) Vol. 11, Issue 501, eaau0416, DOI: 10.1126/scitranslmed.aau0416]

The paper by Lai et al. [1] showed that inhibition of PP-2A with LB100 or LB102 in conjunction with Tyrosine kinase Inhibitors (TKIs) was effective at targeting BCR-ABL + blast cells and insensitive leukemic stem cells (LSCs). Perotti et al. [2] has severely criticised the paper by Lai et al [2]. However, Perotti et al. [2] has failed to appreciate an important principle of the role of PP-2A as a tumor suppressor and its regulation in the cell, namely that in general, PP-2A dephosphoryltes and inactivates enzymes and proteins that upregulate cell proliferation, cell survival, tumorigenic and metastasizing pathways but with a limited number of of enzymes and proteins, PP-2A acts to upregulate them. Thus, PP-2A is a double-edge sword and modulation of its activity must be calibrated empirically. Also, Perotti et al. [2] has misunderstood an important principle of enzyme regulation, namely that PP-2A is regulated by inhibitory and activating molecules and not through "targeting proteins" which has not been scientifically verified. It is submitted that the paper by Lai et al. [1] has strong merit as it shows for the first time that an inhibitor of PP-2A can synergize with a TKI.