Mitotic Errors Promote Genomic Instability and Leukemia in a Novel Mouse Model of Fanconi Anemia

Fanconi anemia (FA) is a disease of genomic instability and cancer. In addition to DNA damage repair, FA pathway proteins are now known to be critical for maintaining faithful chromosome segregation during mitosis. While impaired DNA damage repair has been studied extensively in FA-associated carcin...

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Autores principales:	Donna M. Edwards, Dana K. Mitchell, Zahi Abdul-Sater, Ka-Kui Chan, Zejin Sun, Aditya Sheth, Ying He, Li Jiang, Jin Yuan, Richa Sharma, Magdalena Czader, Pei-Ju Chin, Yie Liu, Guillermo de Cárcer, Grzegorz Nalepa, Hal E. Broxmeyer, D. Wade Clapp, Elizabeth A. Sierra Potchanant
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	Fanconi anemia leukemia spindle assembly checkpoint genomic instability FANCC Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/3f11e067632b4f1cb8c3aaa365e91a9e
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spelling	oai:doaj.org-article:3f11e067632b4f1cb8c3aaa365e91a9e2021-11-05T11:31:47ZMitotic Errors Promote Genomic Instability and Leukemia in a Novel Mouse Model of Fanconi Anemia2234-943X10.3389/fonc.2021.752933https://doaj.org/article/3f11e067632b4f1cb8c3aaa365e91a9e2021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fonc.2021.752933/fullhttps://doaj.org/toc/2234-943XFanconi anemia (FA) is a disease of genomic instability and cancer. In addition to DNA damage repair, FA pathway proteins are now known to be critical for maintaining faithful chromosome segregation during mitosis. While impaired DNA damage repair has been studied extensively in FA-associated carcinogenesis in vivo, the oncogenic contribution of mitotic abnormalities secondary to FA pathway deficiency remains incompletely understood. To examine the role of mitotic dysregulation in FA pathway deficient malignancies, we genetically exacerbated the baseline mitotic defect in Fancc-/- mice by introducing heterozygosity of the key spindle assembly checkpoint regulator Mad2. Fancc-/-;Mad2+/- mice were viable, but died from acute myeloid leukemia (AML), thus recapitulating the high risk of myeloid malignancies in FA patients better than Fancc-/-mice. We utilized hematopoietic stem cell transplantation to propagate Fancc-/-; Mad2+/- AML in irradiated healthy mice to model FANCC-deficient AMLs arising in the non-FA population. Compared to cells from Fancc-/- mice, those from Fancc-/-;Mad2+/- mice demonstrated an increase in mitotic errors but equivalent DNA cross-linker hypersensitivity, indicating that the cancer phenotype of Fancc-/-;Mad2+/- mice results from error-prone cell division and not exacerbation of the DNA damage repair defect. We found that FANCC enhances targeting of endogenous MAD2 to prometaphase kinetochores, suggesting a mechanism for how FANCC-dependent regulation of the spindle assembly checkpoint prevents chromosome mis-segregation. Whole-exome sequencing revealed similarities between human FA-associated myelodysplastic syndrome (MDS)/AML and the AML that developed in Fancc-/-; Mad2+/- mice. Together, these data illuminate the role of mitotic dysregulation in FA-pathway deficient malignancies in vivo, show how FANCC adjusts the spindle assembly checkpoint rheostat by regulating MAD2 kinetochore targeting in cell cycle-dependent manner, and establish two new mouse models for preclinical studies of AML.Donna M. EdwardsDonna M. EdwardsDonna M. EdwardsDana K. MitchellDana K. MitchellZahi Abdul-SaterZahi Abdul-SaterKa-Kui ChanKa-Kui ChanZejin SunAditya ShethAditya ShethYing HeLi JiangJin YuanRicha SharmaRicha SharmaMagdalena CzaderPei-Ju ChinYie LiuGuillermo de CárcerGrzegorz NalepaGrzegorz NalepaGrzegorz NalepaGrzegorz NalepaHal E. BroxmeyerD. Wade ClappD. Wade ClappD. Wade ClappD. Wade ClappElizabeth A. Sierra PotchanantElizabeth A. Sierra PotchanantFrontiers Media S.A.articleFanconi anemialeukemiaspindle assembly checkpointgenomic instabilityFANCCNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENFrontiers in Oncology, Vol 11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Fanconi anemia leukemia spindle assembly checkpoint genomic instability FANCC Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Fanconi anemia leukemia spindle assembly checkpoint genomic instability FANCC Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Donna M. Edwards Donna M. Edwards Donna M. Edwards Dana K. Mitchell Dana K. Mitchell Zahi Abdul-Sater Zahi Abdul-Sater Ka-Kui Chan Ka-Kui Chan Zejin Sun Aditya Sheth Aditya Sheth Ying He Li Jiang Jin Yuan Richa Sharma Richa Sharma Magdalena Czader Pei-Ju Chin Yie Liu Guillermo de Cárcer Grzegorz Nalepa Grzegorz Nalepa Grzegorz Nalepa Grzegorz Nalepa Hal E. Broxmeyer D. Wade Clapp D. Wade Clapp D. Wade Clapp D. Wade Clapp Elizabeth A. Sierra Potchanant Elizabeth A. Sierra Potchanant Mitotic Errors Promote Genomic Instability and Leukemia in a Novel Mouse Model of Fanconi Anemia
description	Fanconi anemia (FA) is a disease of genomic instability and cancer. In addition to DNA damage repair, FA pathway proteins are now known to be critical for maintaining faithful chromosome segregation during mitosis. While impaired DNA damage repair has been studied extensively in FA-associated carcinogenesis in vivo, the oncogenic contribution of mitotic abnormalities secondary to FA pathway deficiency remains incompletely understood. To examine the role of mitotic dysregulation in FA pathway deficient malignancies, we genetically exacerbated the baseline mitotic defect in Fancc-/- mice by introducing heterozygosity of the key spindle assembly checkpoint regulator Mad2. Fancc-/-;Mad2+/- mice were viable, but died from acute myeloid leukemia (AML), thus recapitulating the high risk of myeloid malignancies in FA patients better than Fancc-/-mice. We utilized hematopoietic stem cell transplantation to propagate Fancc-/-; Mad2+/- AML in irradiated healthy mice to model FANCC-deficient AMLs arising in the non-FA population. Compared to cells from Fancc-/- mice, those from Fancc-/-;Mad2+/- mice demonstrated an increase in mitotic errors but equivalent DNA cross-linker hypersensitivity, indicating that the cancer phenotype of Fancc-/-;Mad2+/- mice results from error-prone cell division and not exacerbation of the DNA damage repair defect. We found that FANCC enhances targeting of endogenous MAD2 to prometaphase kinetochores, suggesting a mechanism for how FANCC-dependent regulation of the spindle assembly checkpoint prevents chromosome mis-segregation. Whole-exome sequencing revealed similarities between human FA-associated myelodysplastic syndrome (MDS)/AML and the AML that developed in Fancc-/-; Mad2+/- mice. Together, these data illuminate the role of mitotic dysregulation in FA-pathway deficient malignancies in vivo, show how FANCC adjusts the spindle assembly checkpoint rheostat by regulating MAD2 kinetochore targeting in cell cycle-dependent manner, and establish two new mouse models for preclinical studies of AML.
format	article
author	Donna M. Edwards Donna M. Edwards Donna M. Edwards Dana K. Mitchell Dana K. Mitchell Zahi Abdul-Sater Zahi Abdul-Sater Ka-Kui Chan Ka-Kui Chan Zejin Sun Aditya Sheth Aditya Sheth Ying He Li Jiang Jin Yuan Richa Sharma Richa Sharma Magdalena Czader Pei-Ju Chin Yie Liu Guillermo de Cárcer Grzegorz Nalepa Grzegorz Nalepa Grzegorz Nalepa Grzegorz Nalepa Hal E. Broxmeyer D. Wade Clapp D. Wade Clapp D. Wade Clapp D. Wade Clapp Elizabeth A. Sierra Potchanant Elizabeth A. Sierra Potchanant
author_facet	Donna M. Edwards Donna M. Edwards Donna M. Edwards Dana K. Mitchell Dana K. Mitchell Zahi Abdul-Sater Zahi Abdul-Sater Ka-Kui Chan Ka-Kui Chan Zejin Sun Aditya Sheth Aditya Sheth Ying He Li Jiang Jin Yuan Richa Sharma Richa Sharma Magdalena Czader Pei-Ju Chin Yie Liu Guillermo de Cárcer Grzegorz Nalepa Grzegorz Nalepa Grzegorz Nalepa Grzegorz Nalepa Hal E. Broxmeyer D. Wade Clapp D. Wade Clapp D. Wade Clapp D. Wade Clapp Elizabeth A. Sierra Potchanant Elizabeth A. Sierra Potchanant
author_sort	Donna M. Edwards
title	Mitotic Errors Promote Genomic Instability and Leukemia in a Novel Mouse Model of Fanconi Anemia
title_short	Mitotic Errors Promote Genomic Instability and Leukemia in a Novel Mouse Model of Fanconi Anemia
title_full	Mitotic Errors Promote Genomic Instability and Leukemia in a Novel Mouse Model of Fanconi Anemia
title_fullStr	Mitotic Errors Promote Genomic Instability and Leukemia in a Novel Mouse Model of Fanconi Anemia
title_full_unstemmed	Mitotic Errors Promote Genomic Instability and Leukemia in a Novel Mouse Model of Fanconi Anemia
title_sort	mitotic errors promote genomic instability and leukemia in a novel mouse model of fanconi anemia
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/3f11e067632b4f1cb8c3aaa365e91a9e
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Mitotic Errors Promote Genomic Instability and Leukemia in a Novel Mouse Model of Fanconi Anemia

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