PICH deficiency limits the progression of MYC-induced B-cell lymphoma

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Plk1-interacting checkpoint helicase (PICH) is a DNA translocase involved in resolving ultrafine anaphase DNA bridges and, therefore, is important to safeguard chromosome segregation and stability. PICH is overexpressed in various human cancers, particularly in lymphomas such as Burkitt lymphoma, which is caused by MYC translocations. To investigate the relevance of PICH in cancer development and progression, we have combined novel PICH-deficient mouse models with the Eμ-Myc transgenic mouse model, which recapitulates B-cell lymphoma development. We have observed that PICH deficiency delays the onset of MYC-induced lymphomas in Pich heterozygous females. Moreover, using a Pich conditional knockout mouse model, we have found that Pich deletion in adult mice improves the survival of Eμ-Myc transgenic mice. Notably, we show that Pich deletion in healthy adult mice is well tolerated, supporting PICH as a suitable target for anticancer therapies. Finally, we have corroborated these findings in two human Burkitt lymphoma cell lines and we have found that the death of cancer cells was accompanied by chromosomal instability. Based on these findings, we propose PICH as a potential therapeutic target for Burkitt lymphoma and for other cancers where PICH is overexpressed.
OriginalsprogEngelsk
Artikelnummer16
TidsskriftBlood Cancer Journal
Vol/bind14
Udgave nummer1
Antal sider15
ISSN2044-5385
DOI
StatusUdgivet - 2024

Bibliografisk note

Funding Information:
This work was supported by grants from Danish National Research Foundation (DNRF115), European Research Council (ERC-2015-STG-679068), the Spanish Ministry of Science and Innovation-Agencia Estatal de Investigacion (PID2020-119329RB-I00), the Novo Nordisk Foundation (NNF19OC0055203), and the Junta de Andalucía (P20_00755, PAIDI2020). M.C.-G. was supported with a postdoctoral fellowship from the Junta de Andalucía and the European Social Fund (202099908313734) and with a postdoctoral “Juan de la Cierva” fellowship from the MICINN (FJC2020-045915-I). D.P.-M. was supported with a PhD scholarship from the Lundbeck Foundation (R218-2016-415). L.S.-C. was supported with a Postdoctoral Research Contract from the AECC Scientific Foundation (Grant Number POSTD211274SIMÓ). P.A. was supported with a postdoctoral fellowship from the Junta de Andalucía and the European Social Fund (202099908313486). A.G. is funded with a PhD fellowship from the Junta de Andalucía. E.P. is supported by the HORIZON-MSCA ITN RepliFate (101072903). We thank Prof. Fernandez-Capetillo for kindly providing human lymphoma cell lines. We thank Patricia González from the CNIO Histopathology Core Unit, Irene Delgado, and Alexandra Avram for technical support.

Publisher Copyright:
© 2024, The Author(s).

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