Abstract
Mixed lineage leukemia (MLL) is a distinct and rare form of leukemia which mainly affects children. This aggressive disease arises as a result of rearrangements affecting the MLL(KMT2A) gene located on chromosome 11q23. Despite extensive research to develop a targeted therapy, MLL patients have a poor prognosis and efficacious treatments are needed.
Protein Phosphatase 2A (PP2A) is a crucial regulator of pro‐survival pathways such as Akt, Erk, GSK3‐Beta, which are found constitutively deregulated and hyperactivated in MLL. SET is an endogenous binding partner and inhibitor of PP2A. Phosphorylation of SET at Ser9 regulates its accumulation in the cytosol, where it can form an inhibitory complex with PP2A. Inhibition of PP2A upon SET binding promotes the activation of pro‐survival oncogenic pathways. Conversely, inhibition of SET using the SET antagonist, FTY720, rescues the activity of PP2A reducing malignant proliferation in several forms of solid tumours and leukemia, highlighting SET as an interesting target for therapy.
We characterized for the first time SET molecular profile and regulation in MLL cell lines and primary samples with the aim to explore whether SET could be a novel therapeutic target.
We found that SET is over‐expressed in MLL cell lines and primary samples compared to the healthy controls. Analysis of SET phosporylation and localization confirmed that, in MLL cell lines, SET was phosphorylated on Serine residues and mostly localized within the cytoplasm. We also found that SET formed a protein‐protein interaction complex with PP2A in MLL. In addition, SET knock down largely blocked colony formation in MLL cell lines, whereas it did not affect the ability of non MLL cell lines such as K562 and REH to form colonies in semi‐solid medium. These findings indicate an important role for SET in the self‐renewal of MLL cells. Likewise,the pharmacological inhibitor of SET, FTY720, induced a specific block in proliferation in MLL cell lines, whereas it did not affect non MLL cell lines. In MLL cell lines, FTY720 disrupted SET‐PPP2A complex, it reduced the levels of SET, phospho‐PP2A and phospho ERK, without affecting other PP2A downstream targets, including Akt and GSK3Beta. These results might indicate that ERK pathway is the major pathway regulated by PP2A in MLL cell lines and that a complete deletion of SET would be required to shut down the rest of PP2A targets.
Taken together, our data indicate that inhibition of PP2A by SET is key for the tumorigenic potential of MLL leukemia cells and suggest a potential use of targeting PP2A as a novel therapeutic intervention in MLL.
Protein Phosphatase 2A (PP2A) is a crucial regulator of pro‐survival pathways such as Akt, Erk, GSK3‐Beta, which are found constitutively deregulated and hyperactivated in MLL. SET is an endogenous binding partner and inhibitor of PP2A. Phosphorylation of SET at Ser9 regulates its accumulation in the cytosol, where it can form an inhibitory complex with PP2A. Inhibition of PP2A upon SET binding promotes the activation of pro‐survival oncogenic pathways. Conversely, inhibition of SET using the SET antagonist, FTY720, rescues the activity of PP2A reducing malignant proliferation in several forms of solid tumours and leukemia, highlighting SET as an interesting target for therapy.
We characterized for the first time SET molecular profile and regulation in MLL cell lines and primary samples with the aim to explore whether SET could be a novel therapeutic target.
We found that SET is over‐expressed in MLL cell lines and primary samples compared to the healthy controls. Analysis of SET phosporylation and localization confirmed that, in MLL cell lines, SET was phosphorylated on Serine residues and mostly localized within the cytoplasm. We also found that SET formed a protein‐protein interaction complex with PP2A in MLL. In addition, SET knock down largely blocked colony formation in MLL cell lines, whereas it did not affect the ability of non MLL cell lines such as K562 and REH to form colonies in semi‐solid medium. These findings indicate an important role for SET in the self‐renewal of MLL cells. Likewise,the pharmacological inhibitor of SET, FTY720, induced a specific block in proliferation in MLL cell lines, whereas it did not affect non MLL cell lines. In MLL cell lines, FTY720 disrupted SET‐PPP2A complex, it reduced the levels of SET, phospho‐PP2A and phospho ERK, without affecting other PP2A downstream targets, including Akt and GSK3Beta. These results might indicate that ERK pathway is the major pathway regulated by PP2A in MLL cell lines and that a complete deletion of SET would be required to shut down the rest of PP2A targets.
Taken together, our data indicate that inhibition of PP2A by SET is key for the tumorigenic potential of MLL leukemia cells and suggest a potential use of targeting PP2A as a novel therapeutic intervention in MLL.
| Original language | English |
|---|---|
| Pages (from-to) | 51 |
| Number of pages | 52 |
| Journal | British Journal of Haematology |
| Volume | 189 |
| Issue number | S1 |
| Publication status | Published - 27 Apr 2020 |