PI3Kg/δ and NOTCH1 cross-regulate pathways that define the T-cell acute lymphoblastic leukemia disease signature

Evgeni Efimenko, Utpal P. Dave, Irina V. Lebedeva, Yao Shen, Maria J. Sanchez-Quintero, Daniel Diolaiti, Andrew Kung, Brian J. Lannutti, Jianchung Chen, Ronald Realubit, Zoya Niatsetskaya, Vadim Ten, Charles Karan, Xi Chen, Andrea Califano, Thomas G. Diacovo

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

PI3K/AKT and NOTCH1 signaling pathways are frequently dysregulated in T-cell acute lymphoblastic leukemias (T-ALL). Although we have shown that the combined activities of the class I PI3K isoforms p110g and p110d play a major role in the development and progression of PTEN-null T-ALL, it has yet to be determined whether their contribution to leukemogenic programing is unique from that associated with NOTCH1 activation. Using an Lmo2-driven mouse model of T-ALL in which both the PI3K/AKT and NOTCH1 pathways are aber-rantly upregulated, we now demonstrate that the combined activities of PI3Kg/d have both overlapping and distinct roles from NOTCH1 in generating T-ALL disease signature and in promoting tumor cell growth. Treatment of diseased animals with either a dual PI3Kg/d or a g-secretase inhibitor reduced tumor burden, prolonged survival, and induced proapoptotic pathways. Consistent with their similar biological effects, both inhibitors downregulated genes involved in cMYC-dependent metabolism in gene set enrichment analyses. Furthermore, overexpression of cMYC in mice or T-ALL cell lines conferred resistance to both inhibitors, suggesting a point of pathway convergence. Of note, interrogation of transcriptional regulators and analysis of mitochondrial function showed that PI3Kg/d activity played a greater role in supporting the disease signature and critical bioenergetic pathways. Results provide insight into the interrelationship between T-ALL oncogenic networks and the therapeutic efficacy of dual PI3Kg/d inhibition in the context of NOTCH1 and cMYC signaling.

Original languageEnglish (US)
Pages (from-to)2069-2082
Number of pages14
JournalMolecular cancer therapeutics
Volume16
Issue number10
DOIs
StatePublished - Oct 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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