Constitutive DUSP2 expression enhances lymphoid cell proliferation by activating CDK1 and promotes lymphomagenesis

Abstract

DUSP2 is known as a nuclear dual-specificity phosphatase, highly restricted to immune cells. Its expression is induced by antigenic and mitogenic stimuli and has been implicated in immune cell differentiation and functions. However, its role in immune cell mitotic proliferation and hematologic malignancies has not been rigorously examined. Here, we show DUSP2 is highly expressed in human B-cell, T cell, and other hematologic malignancies. Ablating DUSP2 expression in lymphoma cell lines decreases growth and viability. In mice, transgenic Dusp2 expression promotes B-cell and T cell proliferation, and malignant transformation. Mechanistically, DUSP2 promotes cell cycle progression by activating CDK1 through dephosphorylation at inhibitory Tyr15 and Thr14, which is mediated not by its own phosphatase activity, but instead by a structural motif that recruits CDC25 phosphatases. This work reveals an unexpected oncogenic role for DUSP2 in lymphoid malignancies and the function of a structural motif, which represents an appealing target site for therapeutic intervention.