A Therapeutically Targetable NOTCH1-SIRT1-KAT7 Axis in T-cell Leukemia

Blood Cancer Discov. 2023 Jan 6;4(1):12-33. doi: 10.1158/2643-3230.BCD-22-0098.


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.

Significance: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetyltransferases / metabolism
  • Acetyltransferases / pharmacology
  • Acetyltransferases / therapeutic use
  • Histone Acetyltransferases / metabolism
  • Histone Acetyltransferases / pharmacology
  • Histone Acetyltransferases / therapeutic use
  • Humans
  • Leukemia, T-Cell*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma* / drug therapy
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma* / genetics
  • Receptor, Notch1 / genetics
  • Signal Transduction
  • Sirtuin 1 / genetics
  • Sirtuin 1 / metabolism
  • Sirtuin 1 / pharmacology


  • Receptor, Notch1
  • Sirtuin 1
  • Acetyltransferases
  • SIRT1 protein, human
  • NOTCH1 protein, human
  • KAT7 protein, human
  • Histone Acetyltransferases