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Citations to this article

Hematopoiesis and RAS-driven myeloid leukemia differentially require PI3K isoform p110α
Kira Gritsman, … , Thomas M. Roberts, Jean J. Zhao
Kira Gritsman, … , Thomas M. Roberts, Jean J. Zhao
Published February 24, 2014
Citation Information: J Clin Invest. 2014;124(4):1794-1809. https://doi.org/10.1172/JCI69927.
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Research Article Oncology Article has an altmetric score of 14

Hematopoiesis and RAS-driven myeloid leukemia differentially require PI3K isoform p110α

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Abstract

The genes encoding RAS family members are frequently mutated in juvenile myelomonocytic leukemia (JMML) and acute myeloid leukemia (AML). RAS proteins are difficult to target pharmacologically; therefore, targeting the downstream PI3K and RAF/MEK/ERK pathways represents a promising approach to treat RAS-addicted tumors. The p110α isoform of PI3K (encoded by Pik3ca) is an essential effector of oncogenic KRAS in murine lung tumors, but it is unknown whether p110α contributes to leukemia. To specifically examine the role of p110α in murine hematopoiesis and in leukemia, we conditionally deleted p110α in HSCs using the Cre-loxP system. Postnatal deletion of p110α resulted in mild anemia without affecting HSC self-renewal; however, deletion of p110α in mice with KRASG12D-associated JMML markedly delayed their death. Furthermore, the p110α-selective inhibitor BYL719 inhibited growth factor–independent KRASG12D BM colony formation and sensitized cells to a low dose of the MEK inhibitor MEK162. Furthermore, combined inhibition of p110α and MEK effectively reduced proliferation of RAS-mutated AML cell lines and disease in an AML murine xenograft model. Together, our data indicate that RAS-mutated myeloid leukemias are dependent on the PI3K isoform p110α, and combined pharmacologic inhibition of p110α and MEK could be an effective therapeutic strategy for JMML and AML.

Authors

Kira Gritsman, Haluk Yuzugullu, Thanh Von, Howard Yan, Linda Clayton, Christine Fritsch, Sauveur-Michel Maira, Gregory Hollingworth, Christine Choi, Tulasi Khandan, Mahnaz Paktinat, Rachel O. Okabe, Thomas M. Roberts, Jean J. Zhao

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Total citations by year

Year: 2024 2023 2022 2021 2020 2019 2018 2017 2016 2015 2014 Total
Citations: 2 1 2 3 1 3 1 3 10 5 2 33
Citation information
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Citations to this article in year 2016 (10)

Title and authors Publication Year
Genetics and biology of pancreatic ductal adenocarcinoma
H Ying, P Dey, W Yao, AC Kimmelman, GF Draetta, A Maitra, RA DePinho
Genes & development 2016
Inhibition of the Gab2/PI3K/mTOR signaling ameliorates myeloid malignancy caused by Ptpn11 (Shp2) gain-of-function mutations
W Liu, WM Yu, J Zhang, RJ Chan, ML Loh, Z Zhang, KD Bunting, CK Qu
Leukemia 2016
Targeting the PI3K/Akt pathway in murine MDS/MPN driven by hyperactive Ras
J Akutagawa, TQ Huang, I Epstein, T Chang, M Quirindongo-Crespo, CL Cottonham, M Dail, BS Slusher, LS Friedman, D Sampath, BS Braun
Leukemia 2016
NTRK2 activation cooperates with PTEN deficiency in T-ALL through activation of both the PI3K–AKT and JAK–STAT3 pathways
H Yuzugullu, T Von, LM Thorpe, SR Walker, TM Roberts, DA Frank, JJ Zhao
Cell Discovery 2016
Nf1+/− monocytes/macrophages induce neointima formation via CCR2 activation
WK Bessler, G Kim, FZ Hudson, JA Mund, R Mali, K Menon, R Kapur, DW Clapp, DA Ingram, BK Stansfield
Human Molecular Genetics 2016
Targeting the RAS/MAPK pathway with miR-181a in acute myeloid leukemia
X Huang, S Schwind, R Santhanam, AK Eisfeld, C Chiang, M Lankenau, B Yu, P Hoellerbauer, Y Jin, SS Tarighat, J Khalife, A Walker, D Perrotti, CD Bloomfield, H Wang, RJ Lee, LJ Lee, G Marcucci
Oncotarget 2016
Potent efficacy of combined PI3K/mTOR and JAK or ABL inhibition in murine xenograft models of Ph-like acute lymphoblastic leukemia
SK Tasian, DT Teachey, Y Li, F Shen, RC Harvey, IM Chen, T Ryan, TL Vincent, CL Willman, AE Perl, SP Hunger, ML Loh, M Carroll, SA Grupp
Blood 2016
The Fanconi anemia pathway controls oncogenic response in hematopoietic stem and progenitor cells by regulating PRMT5-mediated p53 arginine methylation
W Du, S Amarachintha, O Erden, A Wilson, Q Pang
Oncotarget 2016
KRAS insertion mutations are oncogenic and exhibit distinct functional properties
Y White, A Bagchi, JV Ziffle, A Inguva, G Bollag, C Zhang, H Carias, D Dickens, M Loh, K Shannon, AJ Firestone
Nature Communications 2016
Rps14 haploinsufficiency causes a block in erythroid differentiation mediated by S100A8 and S100A9
RK Schneider, M Schenone, MV Ferreira, R Kramann, CE Joyce, C Hartigan, F Beier, TH Brümmendorf, U Germing, U Platzbecker, G Büsche, R Knüchel, MC Chen, CS Waters, E Chen, LP Chu, CD Novina, RC Lindsley, SA Carr, BL Ebert
Nature Medicine 2016

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