Title: NUP214-ABL1 mediated cell proliferation in T-cell acute lymphoblastic leukemia is dependent on the LCK kinase and various interacting proteins
Authors: De Keersmaecker, Kim * ×
Porcu, Michaƫl *
Cox, Luk
Girardi, Tiziana
Vandepoel, Roel
Op de Beeck, Joyce
Gielen, Olga
Mentens, Nicole
Bennett, Keiryn L
Hantschel, Oliver #
Issue Date: Jan-2014
Publisher: Il Pensiero Scientifico
Series Title: Haematologica vol:99 issue:1 pages:85-93
Abstract: The NUP214-ABL1 fusion protein is a constitutively active protein tyrosine kinase that is found in 6% of patients with T-cell acute lymphoblastic leukemia and that promotes proliferation and survival of T-lymphoblasts. Although NUP214-ABL1 is sensitive to ABL1 kinase inhibitors, development of resistance to these compounds is a major clinical problem, underlining the need for additional drug targets in the sparsely studied NUP214-ABL1 signaling network. In this work, we identify and validate the SRC family kinase LCK as a protein whose activity is absolutely required for the proliferation and survival of T-cell acute lymphoblastic leukemia cells that depend on NUP214-ABL1 activity. These findings underscore the potential of SRC kinase inhibitors and of the dual ABL/SRC kinase inhibitors dasatinib and bosutinib for treating of NUP214-ABL1 positive T-cell acute lymphoblastic leukemia. In addition, we used mass spectrometry to identify protein interaction partners of NUP214-ABL1. Our results strongly support that the signaling network of NUP214-ABL1 is distinct from that previously reported for BCR-ABL1. Moreover, we identify three NUP214-ABL1 interacting proteins, MAD2L1, NUP155, and SMC4, as strictly required for the proliferation and survival of NUP214-ABL1 positive T-cell acute lymphoblastic leukemia cells. In conclusion, this work identifies LCK, MAD2L1, NUP155 and SMC4 as four new potential drug targets in NUP214-ABL1 positive T-cell acute lymphoblastic leukemia.
ISSN: 0390-6078
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Molecular Biology of Leukemia
* (joint) first author
× corresponding author
# (joint) last author

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