Proteosomal degradation of NSD2 by BRCA1 promotes leukemia cell differentiation

The human myelogenous leukemic cell line, K562 undergoes erythroid differentiation by exposure to hemin. Here, we uncovered NSD2 as an innate erythroid differentiation-related factor through a genome-wide CRISPR library screen and explored the regulatory role of NSD2 during myeloid leukemia cell differentiation. We found that NSD2 stability was disrupted by poly-ubiquitination in differentiated K562 cells. Proteomic analysis revealed an interaction between NSD2 and an E3 ubiquitin ligase, BRCA1, which ubiquitylates NSD on K292. Depletion of BRCA1 stabilized NSD2 protein and suppressed K562 cell differentiation. Furthermore, BRCA1 protein level was decreased in bone marrow tumor, while NSD2 level was elevated. Surprisingly, among BRCA1 mutation(s) discovered in lymphoma patients, BRCA1 K1183R prevented its translocation into the nucleus, failed to reduce NSD2 protein levels in hemin-treated K562 cells and eventually disrupted cell differentiation. Our results indicate the regulation of NSD2 stability by BRCA1-mediated ubiquitination as a potential therapeutic target process in multiple myeloma.