Funding
Basic Research Laboratory (BRL)
American Cancer Society (ACS)
Leukemia and Lymphoma Society (LLS)
Ludwig Institute for Cancer Research (LICR)
Alex's Lemonade Stand Foundation for Childhood Cancer (ALSF)
Children's Leukemia Research Association (CLRA)
Gabrielle's Angel Foundation for Cancer Research (GAFCR)
American Association for Cancer Research (AACR)
Center for Biomedical Informatics and Information Technology, National Cancer Institute (CBIIT)
V Foundation for Cancer Research (VFCR)
New Jersey Commission on Cancer Research (NJCCR)
ARTICLE ABSTRACT
T-cell acute lymphoblastic leukemia (T-ALL) is a NOTCH1-driven disease in need of novel therapies. Here, we identify a NOTCH1–SIRT1–KAT7 link as a therapeutic vulnerability in T-ALL, in which the histone deacetylase SIRT1 is overexpressed downstream of a NOTCH1-bound enhancer. SIRT1 loss impaired leukemia generation, whereas SIRT1 overexpression accelerated leukemia and conferred resistance to NOTCH1 inhibition in a deacetylase-dependent manner. Moreover, pharmacologic or genetic inhibition of SIRT1 resulted in significant antileukemic effects. Global acetyl proteomics upon SIRT1 loss uncovered hyperacetylation of KAT7 and BRD1, subunits of a histone acetyltransferase complex targeting H4K12. Metabolic and gene-expression profiling revealed metabolic changes together with a transcriptional signature resembling KAT7 deletion. Consistently, SIRT1 loss resulted in reduced H4K12ac, and overexpression of a nonacetylatable KAT7-mutant partly rescued SIRT1 loss-induced proliferation defects. Overall, our results uncover therapeutic targets in T-ALL and reveal a circular feedback mechanism balancing deacetylase/acetyltransferase activation with potentially broad relevance in cancer.
We identify a T-ALL axis whereby NOTCH1 activates SIRT1 through an enhancer region, and SIRT1 deacetylates and activates KAT7. Targeting SIRT1 shows antileukemic effects, partly mediated by KAT7 inactivation. Our results reveal T-ALL therapeutic targets and uncover a rheostat mechanism between deacetylase/acetyltransferase activities with potentially broader cancer relevance.This article is highlighted in the In This Issue feature, p. 1
