In our study we found that (1) MSI2 is overexpressed and prognostically significant in DLBCL, (2) MSI2 expression interacts with multiple signaling pathways, including stemness and DNA damage repair in DLBCL, and (3) MSI2 knockdown sensitizes DLBCL to chemotherapy and irradiation. Here, MSI2 is linked to diffuse large B-cell lymphoma.