The ITK-SYK fusion oncogene induces a T-cell lymphoproliferative disease in mice mimicking human disease.
Peripheral T-cell lymphomas (PTCL) constitute a major treatment problem with high mortality rates due to the minimal effectiveness of conventional chemotherapy. Recent findings identified ITK-SYK as the first recurrent translocation in 17% of unspecified PTCLs and showed the overexpression of SYK in more than 90% of PTCLs. Here, we show that the expression of ITK-SYK in the bone marrow of BALB/c mice causes a T-cell lymphoproliferative disease in all transplanted mice within 8 weeks after transplantation. The disease was characterized by the infiltration of spleen, lymph nodes, bone marrow, and skin with CD3+CD4+CD8- and CD3+CD4-CD8- ITK-SYK-positive T-cells accompanied by a systemic inflammatory reaction with upregulation of interleukin 5 and INF-gamma. ITK-SYK-positive T-cells showed enhanced apoptosis resistance and INF-gamma production in vitro. The disease was serially transplantable, inducing clonal T-cell expansion in secondary recipients. The action of ITK-SYK in vivo was dependent on SYK kinase activity and disease development could be inhibited by the treatment of mice with SYK inhibitors. Interestingly, the translocation of ITK-SYK from the membrane to the cytoplasm, using a point mutation in the pleckstrin homology domain (ITK-SYK R29C), did not abolish, but rather, enhanced disease development in transplanted mice. CBL binding was strongly enhanced in membrane-associated ITK-SYK E42K and was causative for delayed disease development. Our results show that ITK-SYK causes a T-cell lymphoproliferative disease in mice, supporting its role in T-cell lymphoma development in humans. Therefore, pharmacologic inhibition of SYK in patients with U-PTCLs carrying the ITK-SYK fusion protein might be an effective treatment strategy.
Dierks
Christine
C
Hematology/Oncology, University of Freiburg, Freiburg, Germany. christine.dierks@uniklinik-freiburg.de
Adrian
Francisco
F
Fisch
Paul
P
Ma
Hong
H
Maurer
Helga
H
Herchenbach
Dieter
D
Forster
Christine Ulrike
CU
Sprissler
Clara
C
Liu
Guoxun
G
Rottmann
Sabine
S
Guo
Gui-Rong
GR
Katja
Zirlik
Z
Veelken
Hendrik
H
Warmuth
Markus
M
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D016026:Bone Marrow Transplantation; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation; D016399:Lymphoma, T-Cell / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008232:Lymphoproliferative Disorders / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D017354:Point Mutation; D011505:Protein-Tyrosine Kinases / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D050721:Proto-Oncogene Proteins c-cbl / Q000378:metabolism; D000072377:Syk Kinase; D013601:T-Lymphocytes / Q000276:immunology
D047908:Intracellular Signaling Peptides and Proteins; D015514:Oncogene Proteins, Fusion; D050721:Proto-Oncogene Proteins c-cbl; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C080813:emt protein-tyrosine kinase; C493849:Cbl protein, mouse