About this Research Topic
The main challenge in treating leukemia is overcoming resistance to chemotherapy. Activation of survival kinases such as AKT is associated with poor overall survival. Mutations of FLT-3, RAS and other up-stream signaling regulators can result in aberrant activation of survival cascades that could promote drug resistance or relapse. However, it is estimated that perhaps half of AML patients lack activating mutations and thus other mechanisms are liklely involved. Survival kinases can be activated when the protein phosphatases that negatively regulate their function are suppressed. Protein Phosphatase 2A (PP2A) targets many kinases in mammalian cells including AKT, PKC, and ERK. Analysis of PP2A in any model disease has been difficult as the enzyme is a hetero-trimer consisting of catalytic (C), scaffold (A), and regulatory (B) subunits. As there are two C isoforms, 2 A isoforms, and at least 21 B isoforms, PP2A is not really a single enzyme but rather a family of possibly 80 variants. While focus on the B subunit has allowed for some insight into regulation of function, a true understanding of the role of PP2A in leukemia is lacking. Furthermore, it is becoming evident that diverse mechanisms that suppress PP2A are commonly present in cancers. SET and CIP2A, two cellular inhibitors of PP2A, have been identified in many cancers including leukemia. In addition, post-translational modification of various PP2A subunits can suppress function. Mutations have been identified in some subunits (e.g. both A variants) and expression of some subunits have been found to be suppressed by microRNAs (e.g. miR-1 and the B56 subunit). Targeting PP2A isoforms for AML therapy is difficult as the objective would be to activate these enzymes in order to suppress survival signaling. While this is a daunting challenge, recent studies with FTY-720 suggest that activation of PP2A by a pharmacological agent is possible. In this research topic, we will review (a) PP2A isoforms and their targets that have been identified in leukemia, (b) the role of SET and CIP2A as inhibitors of PP2A, ( c) genetic suppression of PP2A by mutations, miRs, and epigenetic phenomenon, and (d) strategies to activate PP2A for therapy. Emphasis will be placed on hematologic malignancies including acute and chronic leukemias, myelodysplastic syndrome, and lymphoma. In addition to reviews, we would welcome manuscripts reporting new findings.
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