Breaking the pump: targeting the sodium-potassium pump as a therapeutic strategy in acute myeloid leukemia

In order to identify novel, selective targets for acute myeloid leukemia (AML), we used the Cancer Dependency Map, which provides genome-scale CRISPR/Cas9 screen data in hundreds of cancer cell lines. Here, we identified ATP1B3 as a context-specific dependency that could be therapeutically exploited.

ATP1B3 is the glycoprotein subunit (beta) of the Na/K-ATP pump. Together with the catalytic alpha subunit ATP1A1, it forms a heterodimer located in the plasma membrane, regulating the electrochemical gradient across the membrane.

The 4 beta subunit paralogs show similar expression patterns among tissues, with one exception. ATP1B1 has uniformly low expression in hematol. malig. in comparison to other tumor cell lines. By using CRISPR/Cas9 KO to validate this finding we showed that loss of ATP1B3 in ATP1B1 low AML cells leads to synthetic lethality and lower leukemia burden in a BLI-based orthotopic mouse model of AML. The absence of both paralogs of the beta subunit results in the loss of their common essential binding partner ATP1A1 in hematol. malig., while higher expression of ATP1B1 can stabilize ATP1A1 under the loss of ATP1B3 in solid tumors or ATP1B1 overexpressing cells.

Publication History

Article published online:
17 May 2022