TY - JOUR
T1 - The ribosomal RPL10 R98S mutation drives IRES-dependent BCL-2 translation in T-ALL
AU - Kampen, Kim R.
AU - Sulima, Sergey O.
AU - Verbelen, Benno
AU - Girardi, Tiziana
AU - Vereecke, Stijn
AU - Rinaldi, Gianmarco
AU - Verbeeck, Jelle
AU - Op de Beeck, Joyce
AU - Uyttebroeck, Anne
AU - Meijerink, Jules P.P.
AU - Moorman, Anthony V.
AU - Harrison, Christine J.
AU - Spincemaille, Pieter
AU - Cools, Jan
AU - Cassiman, David
AU - Fendt, Sarah Maria
AU - Vermeersch, Pieter
AU - De Keersmaecker, Kim
N1 - Funding Information:
Funding K.R.K. was supported by the Lady Tata Memorial Trust International Award for research in Leukemia. S.O.S. is recipient of an EMBO long-term postdoctoral fellowship and the EHA José Carreras Junior Research Grant. T.G. was supported by a fellowship “Emma-nuel van der Schueren” from Kom op tegen Kanker. B.V. and S.V. are S.B. PhD fellow at FWO (Nos. 1S07118N and 1S49817N). GR is supported by consecutive PhD fellowships from the Emmanuel van der Schueren—Kom op tegen Kanker foundation and FWO. S.M.F. acknowledges funding support from the Concern Foundation (Conquer Cancer Now) and KU-Leuven Methusalem Co-funding. P. V. and D.C. have senior clinical investigator fellowships of the FWO Vlaanderen. This research was funded by an ERC starting grant (No. 334946), FWO funding (G084013N and 1509814N) and a Stichting Tegen Kanker grant (Grant No. 2012-176 and 2016-775) to K.D.K. and by the leukemia research grant 2017 from the “Me To You” foundation to K.R.K.
Publisher Copyright:
© 2018, Macmillan Publishers Limited, part of Springer Nature.
PY - 2019/2/1
Y1 - 2019/2/1
N2 - The R98S mutation in ribosomal protein L10 (RPL10 R98S) affects 8% of pediatric T-cell acute lymphoblastic leukemia (T-ALL) cases, and was previously described to impair cellular proliferation. The current study reveals that RPL10 R98S cells accumulate reactive oxygen species which promotes mitochondrial dysfunction and reduced ATP levels, causing the proliferation defect. RPL10 R98S mutant leukemia cells can survive high oxidative stress levels via a specific increase of IRES-mediated translation of the anti-apoptotic factor B-cell lymphoma 2 (BCL-2), mediating BCL-2 protein overexpression. RPL10 R98S selective sensitivity to the clinically available Bcl-2 inhibitor Venetoclax (ABT-199) was supported by suppression of splenomegaly and the absence of human leukemia cells in the blood of T-ALL xenografted mice. These results shed new light on the oncogenic function of ribosomal mutations in cancer, provide a novel mechanism for BCL-2 upregulation in leukemia, and highlight BCL-2 inhibition as a novel therapeutic opportunity in RPL10 R98S defective T-ALL.
AB - The R98S mutation in ribosomal protein L10 (RPL10 R98S) affects 8% of pediatric T-cell acute lymphoblastic leukemia (T-ALL) cases, and was previously described to impair cellular proliferation. The current study reveals that RPL10 R98S cells accumulate reactive oxygen species which promotes mitochondrial dysfunction and reduced ATP levels, causing the proliferation defect. RPL10 R98S mutant leukemia cells can survive high oxidative stress levels via a specific increase of IRES-mediated translation of the anti-apoptotic factor B-cell lymphoma 2 (BCL-2), mediating BCL-2 protein overexpression. RPL10 R98S selective sensitivity to the clinically available Bcl-2 inhibitor Venetoclax (ABT-199) was supported by suppression of splenomegaly and the absence of human leukemia cells in the blood of T-ALL xenografted mice. These results shed new light on the oncogenic function of ribosomal mutations in cancer, provide a novel mechanism for BCL-2 upregulation in leukemia, and highlight BCL-2 inhibition as a novel therapeutic opportunity in RPL10 R98S defective T-ALL.
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U2 - 10.1038/s41375-018-0176-z
DO - 10.1038/s41375-018-0176-z
M3 - Article
C2 - 29930300
AN - SCOPUS:85048823355
VL - 33
SP - 319
EP - 332
JO - Leukemia
JF - Leukemia
SN - 0887-6924
IS - 2
ER -