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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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Figure 5

p110α is not essential for HSC self-renewal or for stress hematopoiesis.

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p110α is not essential for HSC self-renewal or for stress hematopoiesis....
(A) Noncompetitive repopulation of BM from pIpC-treated FA/FA;Cre mice or FA/FA littermate controls. PB was collected from transplant recipients at 4, 8, and 16 weeks after transplantation, and donor chimerism was determined by flow cytometry as the frequency of CD45.2+ donor-derived cells. (B) Competitive repopulation using BM from pIpC-treated FA/FA;Cre mice or FA/FA littermate controls, mixed in a 3:1 ratio with competitor BM from WT F1 C57BL/6×B6.SJL mice and injected into lethally irradiated B6.SJL recipients. Donor chimerism was determined as in A. (C) Donor contribution to the Mac1+Gr1+ myeloid and B220+ B cell populations in the PB in competitive repopulation experiments. (D) 5-fluorouracil administration to pIpC-treated FA/FA;Cre mice and FA/FA littermate controls. Statistical analyses were performed using 2-tailed Student’s t test. Experiments were performed twice.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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