Tyrosine phosphorylation of CARM1 promotes its enzymatic activity and alters its target specificity

Coactivator-associated arginine methyltransferase 1 (CARM1) is overexpressed in cancer, and it has emerged as an important target in acute myeloid leukemia and other hematologic malignancies. Janus kinase 2 (JAK2), that is activated by mutation in a variety of myeloid malignancies, can dictate chromatin structure via multiple effects. Here, we find that the hyperactivated JAK2-V617F mutant kinase phosphorylates CARM1, increasing its methyltransferase activity and altering its target specificity. Phospho-CARM1 binds and methylates the RUNX1 transcription factor, and the asymmetric dimethylation of R223 and R319 in RUNX1 is lost in engineered to express only non-phosphorylatable CARM1 mutant proteins in JAK2-V617F+ cell lines. The decreased CARM1 activity found in these cell lines impairs cell-cycle progression and induces apoptosis. We have established a link between activated JAK2 and CARM1 activity, and demonstrate that dual targeting of JAK2 and CARM1 is more effective than monotherapy in phospho-CARM1+ cell lines.