Prolyl 4-hydroxylase 2 promotes B-cell lymphoma progression via hydroxylation of Carabin

B-cell lymphomas are heterogeneous blood disorders with limited therapeutic options, largely because of its propensity to relapse and become refractory to treatments. Carabin, a key suppressor of B cell receptor signaling and proliferation, is inactivated in B-cell lymphoma by unknown mechanisms. Here we identify P4HA2 (Prolyl 4-Hydroxylase 2) as a specific proline hydroxylase of Carabin. Carabin hydroxylation leads to its proteasomal degradation, thereby activating the Ras/ERK pathway and increasing B-cell lymphoma proliferation. P4HA2 is undetectable in normal B cells but up-regulated in the diffuse large B-cell lymphoma (DLBCL), driving Carabin inactivation and lymphoma proliferation. Our results indicate that P4HA2 is a potential prognosis marker for DLBCL and a promising pharmacological target for developing treatment of molecularly stratified B-cell lymphomas.