The Role of MYC and PP2A in the Initiation and Progression of Myeloid Leukemias

Abstract

The MYC transcription factor is one of the best characterized PP2A substrates. Deregulation of the MYC oncogene, along with inactivation of PP2A, are two frequent events in cancer. Both proteins are essential regulators of cell proliferation, apoptosis, and differentiation, and they, directly and indirectly, regulate each other’s activity. Studies in cancer suggest that targeting the MYC/PP2A network is an achievable strategy for the clinic. Here, we focus on and discuss the role of MYC and PP2A in myeloid leukemias.

Targeting Abnormal Hematopoietic Stem Cells in Chronic Myeloid Leukemia and Philadelphia Chromosome-Negative Classical Myeloproliferative Neoplasms

“…PP2A is a serine-threonine phosphatase that acts as a tumour suppressor, contributing to >90% intracellular phosphatase activity alongside PP1 [ 29 , 182 , 183 , 184 , 185 ]. PP2A dephosphorylates Myc, disrupting Myc/MAX interaction and inhibits gene expression for mitochondrial biogenesis.…”

“…PP2A dephosphorylates Myc, disrupting Myc/MAX interaction and inhibits gene expression for mitochondrial biogenesis. BCR-ABL1 oncoprotein amplifies endogenous expression of potent PP2A inhibitors protein SET (SET), cancerous inhibitor of PP2A (CIP2A) and PP2A-Aα that inactivate phosphatase activity, hence, resulting in high levels of Myc and uncontrolled DNA synthesis for LSCs survival and maintenance [ 29 , 182 , 183 , 186 , 187 ]. The Myc/MAX complex can directly bind BCR-ABL1 to upregulate its mRNA and protein content, establishing a positive feedback loop for LSCs [ 182 , 185 ].…”

“…BCR-ABL1 oncoprotein amplifies endogenous expression of potent PP2A inhibitors protein SET (SET), cancerous inhibitor of PP2A (CIP2A) and PP2A-Aα that inactivate phosphatase activity, hence, resulting in high levels of Myc and uncontrolled DNA synthesis for LSCs survival and maintenance [ 29 , 182 , 183 , 186 , 187 ]. The Myc/MAX complex can directly bind BCR-ABL1 to upregulate its mRNA and protein content, establishing a positive feedback loop for LSCs [ 182 , 185 ]. Myc inhibitor 10058-F4 suppressed CIP2A in 80% of CD34 + cells ( p = 0.04) and 85% of K562 cells ( p = 0.01), preventing Myc/MAX interaction and restoring tumour-suppressor functions in vitro K562 and CD34 + cell lines [ 29 , 184 ].…”

Philadelphia Chromosome-Positive Leukemia in the Lymphoid Lineage—Similarities and Differences with the Myeloid Lineage and Specific Vulnerabilities

“…A serine-threonine phosphatase 2A (PP2A), responsible for dephosphorylation of many key cell regulators, has been identified as one of the factors in CML advancement to BP. PP2A has been shown to act as a tumor suppressor in some malignancies and its inactivation has been observed in CML MBP cell line (K562) and primary cells [38,39]. In most cases, PP2A downregulation is not caused by mutations in PP2A-encoding gene, as they are rarely observed in leukemias [38].…”

“…PP2A has been shown to act as a tumor suppressor in some malignancies and its inactivation has been observed in CML MBP cell line (K562) and primary cells [38,39]. In most cases, PP2A downregulation is not caused by mutations in PP2A-encoding gene, as they are rarely observed in leukemias [38]. Conversely, the mechanism turned out to be BCR-ABL1-mediated upregulation of the SET nuclear proto-oncogene (SET) protein, a physiological inhibitor of PP2A [39], thus proving unrestrained BCR-ABL1 activity in triggering BP.…”