TY - JOUR
T1 - POT1 regulates proliferation and confers sexual dimorphism in glioma
AU - Jalali, Ali
AU - Yu, Kwanha
AU - Beechar, Vivek
AU - Huerta, Navish A.Bosquez
AU - Grichuk, Anthony
AU - Mehra, Deepika
AU - Lozzi, Brittney
AU - Kong, Kathleen
AU - Scott, Kenneth L.
AU - Rao, Ganesh
AU - Bainbridge, Matthew N.
AU - Bondy, Melissa L.
AU - Deneen, Benjamin
N1 - Funding Information:
This study was supported by NIH grants K08-NS110976 (to A. Jalali), R01-CA217105 (to M.L. Bondy, B. Deneen, and M.N. Bainbridge), R01-NS094615 (to G. Rao), National Cancer Institute-Cancer Therapeutic Discovery (U01-CA217842 to B. Deneen), National Institute of Health (R50-CA252125 to K. Yu), and the American Cancer Society-Rob Rutherford Glioblastoma Research Postdoctoral Fellowship (PF-15-220-01-TBG to K. Yu). In addition, the authors would like to acknowledge the support provided by the Integrated Microscopy Core at Baylor College of Medicine and the Center for Advanced Microscopy and Image Informatics (CAMII) with funding from NIH (DK56338, CA125123, ES030285), CPRIT (RP150578, RP170719), the Dan L. Duncan Comprehensive Cancer Center, and the John S. Dunn Gulf Coast Consortium for Chemical Genomics.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/5
Y1 - 2021/5
N2 - Germline POT1 mutations are found in a spectrum of cancers and confer increased risk. Recently, we identified a series of novel germline POT1 mutations that predispose carrier families to the development of glioma. Despite these strong associations, how these glioma-associated POT1 mutations contribute to glioma tumorigenesis remains undefined. Here we show that POT1- G95C increases proliferation in glioma-initiating cells in vitro and in progenitor populations in the developing brain. In a native mouse model of glioma, loss of Pot1a/b resulted in decreased survival in females compared with males. These findings were corroborated in human glioma, where low POT1 expression correlated with decreased survival in females. Transcriptomic and IHC profiling of Pot1a/b-deficient glioma revealed that tumors in females exhibited decreased expression of immune markers and increased expression of cell-cycle signatures. Similar sex-dependent trends were observed in human gliomas that had low expression of POT1. Together, our studies demonstrate context-dependent functions for POT1 mutation or loss in driving progenitor proliferation in the developing brain and sexual dimorphism in glioma.
AB - Germline POT1 mutations are found in a spectrum of cancers and confer increased risk. Recently, we identified a series of novel germline POT1 mutations that predispose carrier families to the development of glioma. Despite these strong associations, how these glioma-associated POT1 mutations contribute to glioma tumorigenesis remains undefined. Here we show that POT1- G95C increases proliferation in glioma-initiating cells in vitro and in progenitor populations in the developing brain. In a native mouse model of glioma, loss of Pot1a/b resulted in decreased survival in females compared with males. These findings were corroborated in human glioma, where low POT1 expression correlated with decreased survival in females. Transcriptomic and IHC profiling of Pot1a/b-deficient glioma revealed that tumors in females exhibited decreased expression of immune markers and increased expression of cell-cycle signatures. Similar sex-dependent trends were observed in human gliomas that had low expression of POT1. Together, our studies demonstrate context-dependent functions for POT1 mutation or loss in driving progenitor proliferation in the developing brain and sexual dimorphism in glioma.
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U2 - 10.1158/0008-5472.CAN-20-3755
DO - 10.1158/0008-5472.CAN-20-3755
M3 - Article
C2 - 33782098
AN - SCOPUS:85105923456
SN - 0008-5472
VL - 81
SP - 2703
EP - 2713
JO - Cancer Research
JF - Cancer Research
IS - 10
ER -