From the Biology of PP2A to the PADs for Therapy of Hematologic Malignancies

Abstract

Over the past decades, an emerging role of phosphatases in the pathogenesis of hematologic malignancies and solid tumors has been established. The tumor-suppressor protein phosphatase 2A (PP2A) belongs to the serine-threonine phosphatases family and accounts for the majority of serine-threonine phosphatase activity in eukaryotic cells. Numerous studies have shown that inhibition of PP2A expression and/or function may contribute to leukemogenesis in several hematological malignancies. Likewise, overexpression or aberrant expression of physiologic PP2A inhibitory molecules (e.g., SET and its associated SETBP1 and CIP2A) may turn off PP2A function and participate to leukemic progression. The discovery of PP2A as tumor suppressor has prompted the evaluation of the safety and the efficacy of new compounds, which can restore PP2A activity in leukemic cells. Although further studies are needed to better understand how PP2A acts in the intricate phosphatases/kinases cancer network, the results reviewed herein strongly support the development on new PP2A-activating drugs and the immediate introduction of those available into clinical protocols for leukemia patients refractory or resistant to current available therapies.

Keywords: PADs; PP2A; SET; phosphatases; tumor suppressor.

Figure 1

PP2A networks. PP2A is involved in various cellular signaling including MAPK/ERK, PI3K/AKT, Jak2, and CDK. Thus, the effects of PP2A down-regulation could potentially affect multiple pathways resulting in alteration of apoptosis, cell growth, proliferation, and differentiation in adult cells.

Figure 2

PP2A in CML cells. In CML cells, the BCR–ABL1 and the PP2A pathways are strictly connected. PP2A induces dephosphorylation/inactivation of BCR–ABL1 and Jak2 tyrosine kinases. Conversely, BCR–ABL1 induces SET and CIP2A expression thus increasing the inhibition on PP2A. Jak2 also down-regulates PP2A through SET.