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 - 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
SN - 0887-6924
VL - 33
SP - 319
EP - 332
JO - Leukemia
JF - Leukemia
IS - 2
ER -