Journal article

Impaired ribosome biogenesis checkpoint activation induces p53-dependent MCL-1 degradation and MYC-driven lymphoma death

Ana Domostegui, Suresh Peddigari, Carol A Mercer, Flavia Iannizzotto, Marta L Rodriguez, Marta Garcia-Cajide, Virginia Amador, Sarah T Diepstraten, Gemma L Kelly, Ramon Salazar, Sara C Kozma, Eric P Kusnadi, Jian Kang, Antonio Gentilella, Richard B Pearson, George Thomas, Joffrey Pelletier

BLOOD | AMER SOC HEMATOLOGY | Published : 2021

Abstract

MYC-driven B-cell lymphomas are addicted to increased levels of ribosome biogenesis (RiBi), offering the potential for therapeutic intervention. However, it is unclear whether inhibition of RiBi suppresses lymphomagenesis by decreasing translational capacity and/or by p53 activation mediated by the impaired RiBi checkpoint (IRBC). Here we generated Eμ-Myc lymphoma cells expressing inducible short hairpin RNAs to either ribosomal protein L7a (RPL7a) or RPL11, the latter an essential component of the IRBC. The loss of either protein reduced RiBi, protein synthesis, and cell proliferation to similar extents. However, only RPL7a depletion induced p53-mediated apoptosis through the selective prot..

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Grants

Awarded by National Institutes of Health, National Cancer Institute


Awarded by Marie Curie Action Career Integration Grant from European Commission


Awarded by Asociacion Espanola Contra el Cancer


Awarded by Instituto de Salud Carlos III (ISCIII)-Red Tematica de Investigacion Cooperativa en Cancer (RTICC)


Awarded by Agencia de Gestio d'Ajuts Universitaris i de Recerca (AGAUR)


Awarded by Spanish Ministry of Science and Innovation ISCIII


Awarded by Association pour la Recherche sur le Cancer


Awarded by National Health and Medical Research Council of Australia


Awarded by Cancer Council of Victoria


Awarded by Victorian Cancer Agency


Awarded by Formacion de Personal Investigador (FPI) grant from the Spanish Ministry of Science and Innovation


Awarded by Juan de la Cierva


Awarded by Spanish Ministry of Science and Innovation


Funding Acknowledgements

This work was supported by a grant from the National Institutes of Health, National Cancer Institute (R01-CA158768) and grants from the Spanish Ministry of Science and Innovation (SAF2011-24967, SAF2014-52162-P, and SAF2017-84301-P), the Marie Curie Action Career Integration Grant from European Commission (PCIG10-GA-2011-304160), the Asociacio'n Espanola Contra el Ca'ncer (GCB14-2035), the Instituto de Salud Carlos III (ISCIII)-Red Tema'tica de Investigacio'n Cooperativa en Ca'ncer (RTICC) (RD12/0036/0049), the Agencia de Gestio'd'Ajuts Universitaris i de Recerca (AGAUR) (SGR 870 and SGR 01743), and the Spanish Ministry of Science and Innovation ISCIII (PIE13/00022) (all to G.T.); by fellowships from the Association pour la Recherche sur le Cancer (SAE20140601346) and Juan de la Cierva (FJCI-2014-20422) (J.P.); by project grants from the National Health and Medical Research Council of Australia (1053792 and 1102609) and from the Cancer Council of Victoria (1184873) (R.B.P.); by grants from the Spanish Ministry of Science and Innovation (SAF201784301-P) and Age` ncia de Gestio'd'Ajuts Universitaris i de Recerca (AGAUR) (SGR 01743) (A.G.); by funding from the Victorian Cancer Agency (MCRF 17028) and a Dyson Bequest Fellowship (G.L.K.); and by a Formacio'n de Personal Investigador (FPI) grant from the Spanish Ministry of Science and Innovation (BES-2015-075840) (A.D.). The Spanish Ministry grants are cofunded by the European Regional Development Fund (FEDER).