title: NUP214-ABL1-mediated cell proliferation in T-cell acute lymphoblastic leukemia is dependent on the LCK kinase and various interacting proteins.
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 ABL1/SRC kinase inhibitors dasatinib and bosutinib for the treatment 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 found that three NUP214-ABL1-interacting proteins, MAD2L1, NUP155, and SMC4, are 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.
authors.affiliation: oliver.hantschel@epfl.ch or kim.dekeersmaecker@cme.vib-kuleuven.be.
authors.forename: Kim
authors.initials: K
authors.lastname: De Keersmaecker
authors.forename: Michaël
authors.initials: M
authors.lastname: Porcu
authors.forename: Luk
authors.initials: L
authors.lastname: Cox
authors.forename: Tiziana
authors.initials: T
authors.lastname: Girardi
authors.forename: Roel
authors.initials: R
authors.lastname: Vandepoel
authors.forename: Joyce Op
authors.initials: JO
authors.lastname: de Beeck
authors.forename: Olga
authors.initials: O
authors.lastname: Gielen
authors.forename: Nicole
authors.initials: N
authors.lastname: Mentens
authors.forename: Keiryn L
authors.initials: KL
authors.lastname: Bennett
authors.forename: Oliver
authors.initials: O
authors.lastname: Hantschel
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D055785:Gene Knockdown Techniques; D006801:Humans; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics* / Q000378:metabolism*; D010766:Phosphorylation; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000378:metabolism*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D034622:RNA Interference; D019061:src-Family Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; C521114:NUP214-ABL1 fusion protein, human; D015514:Oncogene Proteins, Fusion; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D019061:src-Family Kinases