KDM6B protects T-ALL cells from NOTCH1-induced oncogenic stress

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm resulting from the malignant transformation of T-cell progenitors. While activating NOTCH1mutations are the dominant genetic drivers of T-ALL, epigenetic dysfunction plays a central role in the pathology of T-ALL and can provide alternative mechanisms to oncogenesis in lieu of or in combination with genetic mutations. The histone demethylase enzyme KDM6A(UTX) is also recurrently mutated in T-ALL patients and functions as a tumor suppressor. However, its gene paralog, KDM6B(JMJD3), is never mutated and can be significantly overexpressed, suggesting it may be necessary for sustaining the disease. Here, we used mouse and human T-ALL models to show that KDM6Bis required for T-ALL development and maintenance. Using NOTCH1gain-of-function retroviral models, mouse cells genetically deficient for Kdm6bwere unable to propagate T-ALL. Inactivating KDM6Bin human T-ALL patient cells by CRISPR/Cas9 showed KDM6B-targeted cells were significantly outcompeted over time. The dependence of T-ALL cells on KDM6Bwas proportional to the oncogenic strength of NOTCH1mutation, with KDM6B required to prevent stress-induced apoptosis from strong NOTCH1 signaling. These studies identify a crucial role for KDM6Bin sustaining NOTCH1-driven T-ALL and implicate KDM6B as a novel therapeutic target in these patients.