Comparison of the Transforming Effect of Different SYK Oncogenes in Vivo Reveals TEL-SYK As Inducer of an MDS/MPS Overlap Syndrome in Mice
Autor: | Christine Dierks, Helga Maurer, Hendrik Veelken, Clara Sprissler, Hassan Jumaa |
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Rok vydání: | 2012 |
Předmět: |
Myeloid
Oncogene biology Immunology Syk chemical and pharmacologic phenomena hemic and immune systems Cell Biology Hematology environment and public health Biochemistry Jurkat cells medicine.anatomical_structure hemic and lymphatic diseases biology.protein medicine Cancer research Bone marrow biological phenomena cell phenomena and immunity Progenitor cell STAT5 Interleukin 3 |
Zdroj: | Blood. 120:1310-1310 |
ISSN: | 1528-0020 0006-4971 |
Popis: | Abstract 1310 The spleen tyrosin kinase (SYK) was shown to be overexpressed in various human hematologic malignancies like B-cell lymphomas and acute myeloid leukemias. There are two known translocations involving the SYK kinase: ITK-SYK and TEL-SYK. ITK-SYK was identified in unspecified peripheral T-cell lymphomas, whereas the TEL-SYK fusion had been discovered in a patient with myelodysplastic syndrome (MDS). Methods: All SYK containing oncogenes, ITK-SYK, TEL-SYK and SYK wt, were cloned into a pMSCV-IRES-GFP retroviral vector. All oncogenes and a GFP control vector were overexpressed in bone marrow of 5-flurouracil-pretreated mice and oncogene containing bone marrow was transplanted into irradiated recipient mice. Disease development was monitored over 1 year. Additionally the three SYK oncogenes were overexpressed in a myeloid (32D), B-lymphoid (BaF3) and T-cell lineage (Jurkat) to monitor cell context specific differences in cell signaling. Results: Here, we demonstrate that the overexpression of 3 SYK containing oncogenes, SYK wt, TEL-SYK and ITK-SYK in a murine bone marrow transplantation model induces the development of 3 different hematologic (pre)diseases. While ITK-SYK exclusively induced T-cell lymphomas in mice, we found that the TEL-SYK fusion induced an MDS/MPS overlapsyndrom. The mice developed an anemia and thrombopenia with signs of dysplasia of megakaryocytes and the erythroid lineage in the bone marrow and spleens. In addition those mice showed a strong expansion of the myeloid lineage, with leucocytosis in the peripheral blood mainly consisting of differentiated neutrophils. The bone marrow shows expansion of differentiated myeloid cells, but also myeloid progenitors and expansion of HSCs. Interestingly, also SYK wt induced a relative expansion of the myeloid compartment without inducing a leucocytosis or a lethal disease indicating a premalignant myeloproliferative state. Only TEL-SYK was able to induce IL-3 independent growth of BaF3- and 32D cells and could activate STAT5, STAT6, ERK, PLCγ2 and SLP76 in those cell lines. SYK and ITK-SYK were able to activate PLCγ2 and SLP76, but no STAT transcription factors. STAT5 activation by TEL-SYK was detectable also in vivo, which might indicate STAT5 as the major driver of TEL-SYK induced transformation. Our results demonstrate, that the various SYK oncogenes can induce different hematologic diseases in mice and reveales TEL-SYK as the first oncogene inducing an MDS/MPS overlap syndrome in mice. Disclosures: No relevant conflicts of interest to declare. |
Databáze: | OpenAIRE |
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