Acute leukemia cells resistant to PI3K/mTOR inhibition display upregulation of P2RY14 expression

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Bibtex

@article{896195aa2e7c4c6ea77d5c88ca80f538,
title = "Acute leukemia cells resistant to PI3K/mTOR inhibition display upregulation of P2RY14 expression",
abstract = "The PI3K/mTOR pathway is the second most frequently deregulated pathway in a majority of cancers such as breast cancer, lung cancer, and melanomas as well as leukemia. Mutations in the genes coding for receptor tyrosine kinases (RTKs) and G-protein-coupled receptors (GPCRs) are quite common in all forms of acute leukemia. This can be a major cause of deregulation of the PI3K-mTOR pathway. To understand how cells display resistance to the dual PI3K/mTOR inhibitor, we used a panel of 25 acute leukemia cell lines. We observed that while a number of cell lines displayed sensitivity to the dual PI3K/mTOR pathway inhibitor PKI-587, many cells displayed substantial resistance. Cells sensitive to PKI-587 also showed aberrant activation of PI3K/mTOR pathway components such as AKT and S6K and also displayed sensitivity to a panel of various other PI3K/mTOR inhibitors. Using RNA sequencing data, we observed that expression of a G protein-coupled receptor, P2RY14, was upregulated nine-fold in cells showing resistance to the PI3K/mTOR inhibitor. P2RY14 has not been much studied in hematologic malignancies. However, this receptor seems to have a role in the localization of hematopoietic stem cells (HSCs) and in promoting regenerative capabilities following injury. We observed that acute lymphoblastic leukemia (ALL) and FLT3-ITD-positive acute myeloid leukemia (AML) patients with higher expression of P2RY14 mRNA displayed relatively poor survival compared to patients carrying lower expression of P2RY14 suggesting a role of P2RY14 in patient survival. To understand the role of this receptor in cell signaling, we used phospho-protein arrays and observed activation of distinct signaling cascades. Furthermore, array data were verified using murine pro-B cell line Ba/F3 stably transfected with P2RY14. We observed that activation of P2RY14 by its ligand, UDP-glucose, resulted in selective induction of ERK1/2 phosphorylation. Taken together, our data suggest that acute leukemia cells resistant to PI3K/mTOR inhibition display upregulation of a GPCR, P2RY14, which has a role in patient survival and also couples to the activation of ERK signaling.",
keywords = "ALL, AML, B-ALL, P2RY14",
author = "Kinjal Shah and Moharram, {Sausan A.} and Kazi, {Julhash U.}",
year = "2018",
month = "6",
day = "19",
doi = "10.1186/s13148-018-0516-x",
language = "English",
volume = "10",
journal = "Clinical Epigenetics",
issn = "1868-7075",
publisher = "BioMed Central",
number = "1",

}