Chapters authored
The Key Role of the Phosphatase PP2A in the Development of Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is a heterogeneous malignant disorder of hematopoietic progenitor cells characterized by the accumulation of several genetic and epigenetic mutations. Despite the progressive understanding of the molecular heterogeneity of the disease, the survival rate of patients older than 60 years old remains poor. Therefore, it is necessary to develop an effective treatment strategy for those patients in order to beat the disease and improve life quality. Reversible phosphorylation has been widely studied over the last years, and the deregulation of kinases and phosphatase have been verified to have a huge impact in leukemogenesis. Inactivation of the tumor-suppressor protein phosphatase 2A (PP2A) is frequent in AML patients, constituting a promising target for cancer therapy. There are several PP2A inactivation mechanisms. However, overexpression of SET or cancerous inhibitors of PP2A, both endogenous inhibitors of PP2A, are recurrent events in AML patients, leading to the inactivation of the phosphatase PP2A. Preclinical studies show that PP2A reactivation using PP2A-activating drugs (PADs) manage to stop the development of the disease, and its combination with conventional chemotherapy and tyrosine kinase inhibitors have a synergistic cytotoxic effects. Recent studies have demonstrated that specifically activation of PP2A subunits, target crucial pathogenic drivers, increasing the efficacy of conventional treatments and opening new possibilities for personalized treatment in AML patients, especially in cases of PP2A deregulation. Here, we review the role of PP2A in AML as well as its drugable options.
Part of the book: Acute Leukemias