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Therapeutic targeting of ACLY in T-ALL in vivo .

Victoria da Silva-DizAmartya SinghOlga LanchoMaya AleksandrovaKomal MandleywalaPatricia Renck NunesJesminara KhatunOekyung KimEric N ChilesXiaoyang SuHossein KhiabanianKathryn E WellenDaniel Herranz
Published in: bioRxiv : the preprint server for biology (2023)
T-cell Acute Lymphoblastic Leukemia (T-ALL) is a hematological malignancy in need of novel therapeutic approaches. Here, we identify the ATP-citrate lyase ACLY as a novel therapeutic target in T-ALL. Our results show that ACLY is overexpressed in T-ALL, and its expression correlates with NOTCH1 activity. To test the effects of ACLY in leukemia progression and the response to NOTCH1 inhibition, we developed an isogenic model of NOTCH1-induced Acly conditional knockout leukemia. Importantly, we observed intrinsic antileukemic effects upon loss of ACLY, which further synergized with NOTCH1 inhibition in vivo . Gene expression profiling analyses showed that the transcriptional signature of ACLY loss very significantly correlates with the signature of NOTCH1 inhibition in vivo , with significantly downregulated pathways related to oxidative phosphorylation, electron transport chain, ribosomal biogenesis and nucleosome biology. Consistently, metabolomic profiling upon ACLY loss revealed a metabolic crisis with accumulation of nucleotide intermediates and reduced levels of several amino acids. Overall, our results identify a link between NOTCH1 and ACLY and unveil ACLY as a novel promising target for T-ALL treatment.
Keyphrases
  • cell proliferation
  • acute lymphoblastic leukemia
  • public health
  • acute myeloid leukemia
  • genome wide
  • oxidative stress
  • amino acid
  • poor prognosis
  • heat stress