Depletion of STAT5 blocks TEL–SYK-induced APMF-type leukemia with myelofibrosis and myelodysplasia in mice
| Autor: | Justus Duyster, Konrad Aumann, Christine Dierks, Sandra Kissel, Tilman Brummer, Tony Andreas Müller, H Jumaa, Dimitri Belenki, Clara Sprissler, Dietmar Pfeifer, J Alexandrovski, J Hülsdünker, H Maurer, Claudius Klein |
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| Jazyk: | angličtina |
| Rok vydání: | 2014 |
| Předmět: |
Male
Myeloid Oncogene Proteins Fusion Syk chemical and pharmacologic phenomena Erythroid dysplasia environment and public health Cell Line Mice hemic and lymphatic diseases STAT5 Transcription Factor Medicine Animals Syk Kinase Myelofibrosis Mice Inbred BALB C Proto-Oncogene Proteins c-ets business.industry Intracellular Signaling Peptides and Proteins Myeloid leukemia hemic and immune systems Hematology Protein-Tyrosine Kinases medicine.disease Lymphoma Repressor Proteins Leukemia Leukemia Myeloid Acute medicine.anatomical_structure Oncology Primary Myelofibrosis Myelodysplastic Syndromes Immunology Original Article Bone marrow biological phenomena cell phenomena and immunity business Gene Deletion |
| Zdroj: | Blood Cancer Journal |
| ISSN: | 2044-5385 |
| Popis: | The spleen tyrosine kinase (SYK) was identified as an oncogenic driver in a broad spectrum of hematologic malignancies. The in vivo comparison of three SYK containing oncogenes, SYK(wt), TEL-SYK and IL-2-inducible T-cell kinase (ITK)-SYK revealed a general myeloexpansion and the establishment of three different hematologic (pre)diseases. SYK(wt) enhanced the myeloid and T-cell compartment, without leukemia/lymphoma development. ITK-SYK caused lethal T-cell lymphomas and the cytoplasmic TEL-SYK fusion induced an acute panmyelosis with myelofibrosis-type acute myeloid leukemia (AML) with up to 50% immature megakaryoblasts infiltrating bone marrow, spleen and liver, additional MPN features (myelofibrosis and granulocyte expansion) and MDS stigmata with megakaryocytic and erythroid dysplasia. LKS cells were reduced and all subsets (LT/ST/MPP) showed reduced proliferation rates. SYK inhibitor treatment (R788) of diseased TEL-SYK mice reduced leukocytosis, spleen and liver infiltration, enhanced the hematocrit and prolonged survival time, but could not significantly reduce myelofibrosis. Stat5 was identified as a major downstream mediator of TEL-SYK in vitro as well as in vivo. Consequently, targeted deletion of Stat5 in vivo completely abrogated TEL-SYK-induced AML and myelofibrosis development, proving Stat5 as a major driver of SYK-induced transformation. Our experiments highlight the important role of SYK in AML and myelofibrosis and prove SYK and STAT5 inhibitors as potent treatment options for those diseases. |
| Databáze: | OpenAIRE |
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