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

Authors :
Nancy Issa
Hassan Bjeije
Elisabeth Wilson
Aishwarya Krishnan
Wangisa Dunuwille
Tyler Parsons
Christine Zhang
Wentao Han
Andrew Young
Zhizhong Ren
Kai Ge
Eunice Wang
Andrew Weng
Amanda Cashen
David Spencer
Grant Challen
Publication Year :
2022
Publisher :
Research Square Platform LLC, 2022.

Abstract

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematopoietic neoplasm resulting from the malignant transformation of T-cell progenitors. While activating NOTCH1 mutations 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 KDM6B is required for T-ALL development and maintenance. Using NOTCH1 gain-of-function retroviral models, mouse cells genetically deficient for Kdm6b were unable to propagate T-ALL. Inactivating KDM6B in human T-ALL patient cells by CRISPR/Cas9 showed KDM6B-targeted cells were significantly outcompeted over time. The dependence of T-ALL cells on KDM6B was proportional to the oncogenic strength of NOTCH1 mutation, with KDM6B required to prevent stress-induced apoptosis from strong NOTCH1 signaling. These studies identify a crucial role for KDM6B in sustaining NOTCH1-driven T-ALL and implicate KDM6B as a novel therapeutic target in these patients.

Details

Database :
OpenAIRE
Accession number :
edsair.doi...........0ad3c6e2b3760b1a82a8134ff929b7bb
Full Text :
https://doi.org/10.21203/rs.3.rs-2251777/v1