Discovery of a novel potentially transforming somatic mutation in CSF2RB gene in breast cancer

Abstract The colony stimulating factor 2 receptor subunit beta (CSF2RB) is the common signaling subunit of the cytokine receptors for IL‐3, IL‐5, and GM‐CSF. Several studies have shown that spontaneous and random mutants of CSF2RB can lead to ligand independence in vitro. To date, no report(s) have...

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Autores principales:	Mamoon Rashid, Rizwan Ali, Bader Almuzzaini, Hao Song, Alshaimaa AlHallaj, Al Abdulrahman Abdulkarim, Omar Mohamed Baz, Hajar Al Zahrani, Muhammed Mustafa Sabeena, Wardah Alharbi, Mohamed Hussein, Mohamed Boudjelal
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	breast cancer breast cancer cell line CSF2RB‐activating mutation cytokine receptor hβc receptor JAK2 inhibitor Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/301f3883e51a43d9bf7f977108cd73df
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spelling	oai:doaj.org-article:301f3883e51a43d9bf7f977108cd73df2021-11-22T09:08:48ZDiscovery of a novel potentially transforming somatic mutation in CSF2RB gene in breast cancer2045-763410.1002/cam4.4106https://doaj.org/article/301f3883e51a43d9bf7f977108cd73df2021-11-01T00:00:00Zhttps://doi.org/10.1002/cam4.4106https://doaj.org/toc/2045-7634Abstract The colony stimulating factor 2 receptor subunit beta (CSF2RB) is the common signaling subunit of the cytokine receptors for IL‐3, IL‐5, and GM‐CSF. Several studies have shown that spontaneous and random mutants of CSF2RB can lead to ligand independence in vitro. To date, no report(s) have been shown for the presence of potentially transforming and oncogenic CSF2RB mutation(s) clinically in cancer patients until the first reported case of a leukemia patient in 2016 harboring a germline‐activating mutation (R461C). We combined exome sequencing, pathway analyses, and functional assays to identify novel somatic mutations in KAIMRC1 cells and breast tumor specimen. The patient’s peripheral blood mononuclear cell (PBMC) exome served as a germline control in the identification of somatic mutations. Here, we report the discovery of a novel potentially transforming and oncogenic somatic mutation (S230I) in the CSF2RB gene of a breast cancer patient and the cell line, KAIMRC1 established from her breast tumor tissue. KAIMRC1 cells are immortalized and shown to survive and proliferate in ligand starvation condition. Immunoblot analysis showed that mutant CSF2RB signals through JAK2/STAT and PI3K/mTOR pathways in ligand starvation conditions. Screening a small molecule kinase inhibitor library revealed potent JAK2 inhibitors against KAIMRC1 cells. We, for the first time, identified a somatic, potentially transforming, and oncogenic CSF2RB mutation (S230I) in breast cancer patients that seem to be an actionable mutation leading to the development of new therapeutics for breast cancer.Mamoon RashidRizwan AliBader AlmuzzainiHao SongAlshaimaa AlHallajAl Abdulrahman AbdulkarimOmar Mohamed BazHajar Al ZahraniMuhammed Mustafa SabeenaWardah AlharbiMohamed HusseinMohamed BoudjelalWileyarticlebreast cancerbreast cancer cell lineCSF2RB‐activating mutationcytokine receptorhβc receptorJAK2 inhibitorNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENCancer Medicine, Vol 10, Iss 22, Pp 8138-8150 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	breast cancer breast cancer cell line CSF2RB‐activating mutation cytokine receptor hβc receptor JAK2 inhibitor Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	breast cancer breast cancer cell line CSF2RB‐activating mutation cytokine receptor hβc receptor JAK2 inhibitor Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Mamoon Rashid Rizwan Ali Bader Almuzzaini Hao Song Alshaimaa AlHallaj Al Abdulrahman Abdulkarim Omar Mohamed Baz Hajar Al Zahrani Muhammed Mustafa Sabeena Wardah Alharbi Mohamed Hussein Mohamed Boudjelal Discovery of a novel potentially transforming somatic mutation in CSF2RB gene in breast cancer
description	Abstract The colony stimulating factor 2 receptor subunit beta (CSF2RB) is the common signaling subunit of the cytokine receptors for IL‐3, IL‐5, and GM‐CSF. Several studies have shown that spontaneous and random mutants of CSF2RB can lead to ligand independence in vitro. To date, no report(s) have been shown for the presence of potentially transforming and oncogenic CSF2RB mutation(s) clinically in cancer patients until the first reported case of a leukemia patient in 2016 harboring a germline‐activating mutation (R461C). We combined exome sequencing, pathway analyses, and functional assays to identify novel somatic mutations in KAIMRC1 cells and breast tumor specimen. The patient’s peripheral blood mononuclear cell (PBMC) exome served as a germline control in the identification of somatic mutations. Here, we report the discovery of a novel potentially transforming and oncogenic somatic mutation (S230I) in the CSF2RB gene of a breast cancer patient and the cell line, KAIMRC1 established from her breast tumor tissue. KAIMRC1 cells are immortalized and shown to survive and proliferate in ligand starvation condition. Immunoblot analysis showed that mutant CSF2RB signals through JAK2/STAT and PI3K/mTOR pathways in ligand starvation conditions. Screening a small molecule kinase inhibitor library revealed potent JAK2 inhibitors against KAIMRC1 cells. We, for the first time, identified a somatic, potentially transforming, and oncogenic CSF2RB mutation (S230I) in breast cancer patients that seem to be an actionable mutation leading to the development of new therapeutics for breast cancer.
format	article
author	Mamoon Rashid Rizwan Ali Bader Almuzzaini Hao Song Alshaimaa AlHallaj Al Abdulrahman Abdulkarim Omar Mohamed Baz Hajar Al Zahrani Muhammed Mustafa Sabeena Wardah Alharbi Mohamed Hussein Mohamed Boudjelal
author_facet	Mamoon Rashid Rizwan Ali Bader Almuzzaini Hao Song Alshaimaa AlHallaj Al Abdulrahman Abdulkarim Omar Mohamed Baz Hajar Al Zahrani Muhammed Mustafa Sabeena Wardah Alharbi Mohamed Hussein Mohamed Boudjelal
author_sort	Mamoon Rashid
title	Discovery of a novel potentially transforming somatic mutation in CSF2RB gene in breast cancer
title_short	Discovery of a novel potentially transforming somatic mutation in CSF2RB gene in breast cancer
title_full	Discovery of a novel potentially transforming somatic mutation in CSF2RB gene in breast cancer
title_fullStr	Discovery of a novel potentially transforming somatic mutation in CSF2RB gene in breast cancer
title_full_unstemmed	Discovery of a novel potentially transforming somatic mutation in CSF2RB gene in breast cancer
title_sort	discovery of a novel potentially transforming somatic mutation in csf2rb gene in breast cancer
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/301f3883e51a43d9bf7f977108cd73df
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Discovery of a novel potentially transforming somatic mutation in CSF2RB gene in breast cancer

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