ABL1 fusions in T-cell acute lymphoblastic leukemia.
Mutant tyrosine kinases are common in cancer and can be therapeutically targeted with kinase inhibitors. To obtain insight in the contribution of activated kinases to the pathogenesis ofT-cell acute lymphoblastic leukemia (T-ALL), we studied the NUP214-ABL1 fusion gene that is found in 6% of T-ALL and EML1-ABL1 that we identified in one T-ALL patient. NUP214-ABL1 and EML1-ABL1 display constitutive kinase activity and are sensitive to the kinase inhibitor imatinib. Both proteins transform hematopoietic cells and we established mouse models of EML1-ABL1 and NUP214-ABL1 induced T-ALL. Interestingly, whereas EML1-ABL1 activity requires homo-oligomerization via its coiled coil domain, activity of NUP214-ABL1 depends on its cellular localization to the nuclear pore complexes. These results for NUP214-ABL1 delineate a novel mechanism for fusion kinase activation in cancer and provide new options to interfere with NUP214-ABL1 activity. T-ALL development requires accumulation of different mutations. Little is known about the cooperation between the mutations and about their sequence of accumulation. We provide evidence that tyrosine kinase mutations occur late in T-ALL development, suggesting limited potential for kinase inhibitor monotherapy. We therefore combined NUP214-ABL1 inhibition with other therapies and show that inhibition of NUP214-ABL1 and NOTCH1 in vitro can result in synergistic effects. Further validation of these and other combination therapies requires animal models containing several of the mutations in T-ALL and thus reflecting the multistep oncogenic process of human T-ALL genesis. The models for ABL1 fusion induced T-ALL will serve as starting point here.
De Keersmaecker
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Center for Human Genetics, Katholieke Universiteit Leuven, VIB Department of Molecular and Developmental Genetics, Campus Gasthuisberg O&N1 box 602, Herestraat 49, B-3000 Leuven.
D001549:Benzamides; D016313:Genes, abl; D006801:Humans; D000068877:Imatinib Mesylate; D015458:Leukemia, T-Cell / Q000235:genetics* / Q000378:metabolism*; D028861:Nuclear Pore Complex Proteins / Q000037:antagonists & inhibitors / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology
D001549:Benzamides; C501947:EML1-ABL1 fusion protein, human; C085914:NUP214 protein, human; D028861:Nuclear Pore Complex Proteins; D015514:Oncogene Proteins, Fusion; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases