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 language | English (US) |
|---|---|
| Pages (from-to) | 2069-2082 |
| Number of pages | 14 |
| Journal | Molecular Cancer Therapeutics |
| Volume | 16 |
| Issue number | 10 |
| DOIs | |
| State | Published - Oct 1 2017 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
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PI3Kg/δ and NOTCH1 cross-regulate pathways that define the T-cell acute lymphoblastic leukemia disease signature. / Efimenko, Evgeni; Dave, Utpal P.; Lebedeva, Irina V.; Shen, Yao; Sanchez-Quintero, Maria J.; Diolaiti, Daniel; Kung, Andrew; Lannutti, Brian J.; Chen, Jianchung; Realubit, Ronald; Niatsetskaya, Zoya; Ten, Vadim; Karan, Charles; Chen, Xi; Califano, Andrea; Diacovo, Thomas G.
In: Molecular Cancer Therapeutics, Vol. 16, No. 10, 01.10.2017, p. 2069-2082.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - PI3Kg/δ and NOTCH1 cross-regulate pathways that define the T-cell acute lymphoblastic leukemia disease signature
AU - Efimenko, Evgeni
AU - Dave, Utpal P.
AU - Lebedeva, Irina V.
AU - Shen, Yao
AU - Sanchez-Quintero, Maria J.
AU - Diolaiti, Daniel
AU - Kung, Andrew
AU - Lannutti, Brian J.
AU - Chen, Jianchung
AU - Realubit, Ronald
AU - Niatsetskaya, Zoya
AU - Ten, Vadim
AU - Karan, Charles
AU - Chen, Xi
AU - Califano, Andrea
AU - Diacovo, Thomas G.
PY - 2017/10/1
Y1 - 2017/10/1
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85030623404&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-17-0141
DO - 10.1158/1535-7163.MCT-17-0141
M3 - Article
C2 - 28716817
AN - SCOPUS:85030623404
VL - 16
SP - 2069
EP - 2082
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
SN - 1535-7163
IS - 10
ER -