Metformin inhibits JAK2V617F activity in MPN cells by activating AMPK and PP2A complexes containing the B56α subunit.

Metformin suppresses the growth of a variety of malignant hematologic cells. It is widely accepted that metformin inhibits the growth of malignant cells primarily by suppressing the mTOR pathway or regulating autophagy. In contrast, we found another possible mechanism that inhibits the growth of malignant cells, suppression of the activity of the oncogenic kinase JAK2V617F. We identified at least two distinct mechanisms involved in metformin-induced JAK2V617F inhibition. First, metformin increases reactive oxygen species levels in these cells, leading to the inhibition of SHP-2, a positive regulator of JAK2V617F. These effects of metformin require AMPK. Second, metformin activates protein tyrosine phosphatase PP2A, a negative regulator of JAK2V617F. Furthermore, we determined that among the numerous PP2A subfamily members, the PP2A complex containing the B56α subunit is responsible for the inhibition of JAK2V617F. In contrast, the B56α-containing PP2A complex functions as a positive regulator of JAK2V617F by inhibiting AMPK. Finally, we determined that metformin enhances the antileukemic action of ruxolitinib in HEL and SET-2 cells. Our present observations suggest that the combination of metformin with ruxolitinib might be a new therapeutic option for treating JAK2V617F-induced myeloproliferative neoplasms. In addition, activators specific for PP2A complexes containing the B56α subunit may be useful for the treatment of JAK2V617F-induced myeloproliferative neoplasms.