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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
This citation data is accumulated from CrossRef, which receives citation information from participating publishers, including this journal. Not all publishers participate in CrossRef, so this information is not comprehensive. Additionally, data may not reflect the most current citations to this article, and the data may differ from citation information available from other sources (for example, Google Scholar, Web of Science, and Scopus).

Citations to this article in year 2015 (5)

Title and authors Publication Year
Outlook on PI3K/AKT/mTOR inhibition in acute leukemia
L Fransecky, LH Mochmann, CD Baldus
Molecular and Cellular Therapies 2015
Targeting mTOR signaling pathways and related negative feedback loops for the treatment of acute myeloid leukemia
BA Carneiro, JB Kaplan, JK Altman, FJ Giles, LC Platanias
Cancer biology & therapy 2015
PI3K isoform-selective inhibitors: next-generation targeted cancer therapies
X Wang, J Ding, L Meng
Acta Pharmacologica Sinica 2015
A PI3K p110β–Rac signalling loop mediates Pten-loss-induced perturbation of haematopoiesis and leukaemogenesis
H Yuzugullu, L Baitsch, T Von, A Steiner, H Tong, J Ni, LK Clayton, R Bronson, TM Roberts, K Gritsman, JJ Zhao
Nature Communications 2015
Dual targeting of acute myeloid leukemia progenitors by catalytic mTOR inhibition and blockade of the p110α subunit of PI3 kinase
Colamonici M, Blyth G, Saleiro D, Szilard A, Bliss-Moreau M, Giles FJ, Altman JK, Beauchamp EM, Platanias LC
Oncotarget 2015

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