We show that p38β overexpression is a recurrent event in AML cases that contributes to PP2A inactivation by regulating the SET oncoprotein through two mechanisms: (i) p38β controls CK2-mediated phosphorylation of SET facilitating its cytoplasmic localization, and (ii) p38β binds to and stabilizes SET in the cytoplasm. The gene discussed is MAPK11; the disease is acute myeloid leukemia.