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

Shah, Kinjal LU ; Moharram, Sausan A. LU and Kazi, Julhash U. LU orcid (2018) In Clinical Epigenetics 10(1).
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... (More)

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.

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author
; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
ALL, AML, B-ALL, P2RY14
in
Clinical Epigenetics
volume
10
issue
1
article number
83
publisher
BioMed Central (BMC)
external identifiers
  • pmid:29951132
  • scopus:85048841425
ISSN
1868-7075
DOI
10.1186/s13148-018-0516-x
language
English
LU publication?
yes
id
896195aa-2e7c-4c6e-a77d-5c88ca80f538
date added to LUP
2018-07-05 12:52:54
date last changed
2023-01-22 22:55:28
@article{896195aa-2e7c-4c6e-a77d-5c88ca80f538,
  abstract     = {{<p>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.</p>}},
  author       = {{Shah, Kinjal and Moharram, Sausan A. and Kazi, Julhash U.}},
  issn         = {{1868-7075}},
  keywords     = {{ALL; AML; B-ALL; P2RY14}},
  language     = {{eng}},
  month        = {{06}},
  number       = {{1}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{Clinical Epigenetics}},
  title        = {{Acute leukemia cells resistant to PI3K/mTOR inhibition display upregulation of P2RY14 expression}},
  url          = {{http://dx.doi.org/10.1186/s13148-018-0516-x}},
  doi          = {{10.1186/s13148-018-0516-x}},
  volume       = {{10}},
  year         = {{2018}},
}