Efimenko, EvgeniDavé, Utpal P.Lebedeva, Irina V.Shen, YaoSanchez-Quintero, Maria J.Diolaiti, DanielKung, AndrewLannutti, Brian J.Chen, JianchungRealubit, RonaldNiatsetskiya, ZoyaTen, VadimKaran, CharlesChen, XiCalifano, AndreaDiacovo, Thomas G.2018-04-262018-04-262017-10Efimenko, E., Davé, U. P., Lebedeva, I. V., Shen, Y., Sanchez-Quintero, M. J., Diolaiti, D., … Diacovo, T. G. (2017). PI3Kγ/δ and NOTCH1 Cross-Regulate Pathways That Define the T-cell Acute Lymphoblastic Leukemia Disease Signature. Molecular Cancer Therapeutics, 16(10), 2069–2082. https://doi.org/10.1158/1535-7163.MCT-17-0141https://hdl.handle.net/1805/15918PI3K/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 p110γ and p110δ 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 aberrantly upregulated, we now demonstrate that the combined activities of PI3Kγ/δ 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 PI3Kγ/δ or a γ-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 PI3Kγ/δ 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 PI3Kγ/δ inhibition in the context of NOTCH1 and cMYC signaling.enPublisher PolicyT-ALLGSIPI3Kγ/δArticle