We propose that ARID5B also functions as a gatekeeper protecting Pre-B cells from malignant transformation based on our findings that i) Arid5b deficiency enhances proliferation of Pre-B cells with increased metabolism; ii) ARID5B expression is reduced in B-ALL cells compared to normal CD19+ B cells; and iii) reduced ARID5B expression increases the risk of mortality. Here, ARID5B is linked to acute lymphoblastic leukemia.