A therapeutically targetable NOTCH1-SIRT1-KAT7 axis in T-cell Leukemia

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 SIRT1 is overexpressed downstream of a novel NOTCH1-bound enhancer. SIRT1 loss impairs leukemia generation, while SIRT1 overexpression accelerates leukemia and confers resistance to NOTCH1 inhibition in a deacetylase-dependent manner. Moreover, secondary SIRT1 loss extends survival and synergizes with NOTCH1 inhibition. 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 a metabolic crisis together with a transcriptional signature resembling KAT7 deletion. Consistently, SIRT1 loss resulted in reduced H4K12ac, and overexpression of a non-acetylatable KAT7 mutant partly rescued SIRT1 loss-induced proliferation defects. The newly unveiled NOTCH1-SIRT1-KAT7 axis uncovers novel therapeutic targets in T-ALL and reveals a circular feedback mechanism balancing deacetylase/acetyltransferase activation with potentially broad relevance in cancer.

Therapeutic targeting of ACLY in T-ALLin vivo

“…RNA library preparations and next-generation sequencing were performed using Illumina Next-Seq platform (Illumina). We estimated gene-level raw counts and performed differential expression and/or GSEA analyses as previously described 11 .…”

“…Next, we hypothesized that targeting ACLY in T-ALL might confer therapeutic effects. To test this hypothesis, we generated a model of NOTCH1-induced Acly conditional knockout leukemia using a well-established protocol 4,6,11,12 of retroviral transduction of an oncogenic form of NOTCH1 in bone marrow progenitor cells from Acly conditional knockout mice, followed by transplantation into lethally irradiated recipients (Fig. 2A).…”