JAK inhibitors suppress t(8;21) fusion protein-induced leukemia
| Autor: | Xiuli Cong, Justin H. Hickman, Russel C. DeKelver, Luke F. Peterson, Dong-Er Zhang, Miao Chia Lo, Denise Niewerth, Ming Yan |
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| Rok vydání: | 2013 |
| Předmět: |
Cancer Research
Chromosomes Human Pair 21 medicine.medical_treatment Apoptosis AML1-ETO9a Biology Translocation Genetic Article stat Targeted therapy Mice 03 medical and health sciences 0302 clinical medicine hemic and lymphatic diseases medicine Animals Humans AML1-ETO Protein Kinase Inhibitors t(8 21) Cells Cultured DNA Primers Janus Kinases 030304 developmental biology 0303 health sciences Leukemia Base Sequence JAK2 inhibitors JAK-STAT signaling pathway Myeloid leukemia Hematology Flow Cytometry medicine.disease JAK/STAT Fusion protein Molecular biology 3. Good health Mice Inbred C57BL Cytokine Oncology 030220 oncology & carcinogenesis Cancer research Janus kinase Chromosomes Human Pair 8 |
| Zdroj: | Leukemia |
| ISSN: | 1476-5551 0887-6924 |
| DOI: | 10.1038/leu.2013.197 |
| Popis: | Oncogenic mutations in components of the JAK/STAT pathway, including those in cytokine receptors and JAKs, lead to increased activity of downstream signaling and are frequently found in leukemia and other hematological disorders. Thus, small-molecule inhibitors of this pathway have been the focus of targeted therapy in these hematological diseases. We previously showed that t(8;21) fusion protein acute myeloid leukemia (AML)1-ETO and its alternatively spliced variant AML1-ETO9a (AE9a) enhance the JAK/STAT pathway via downregulation of CD45, a negative regulator of this pathway. To investigate the therapeutic potential of targeting JAK/STAT in t(8;21) leukemia, we examined the effects of a JAK2-selective inhibitor TG101209 and a JAK1/2-selective inhibitor INCB18424 on t(8;21) leukemia cells. TG101209 and INCB18424 inhibited proliferation and promoted apoptosis of these cells. Furthermore, TG101209 treatment in AE9a leukemia mice reduced tumor burden and significantly prolonged survival. TG101209 also significantly impaired the leukemia-initiating potential of AE9a leukemia cells in secondary recipient mice. These results demonstrate the potential therapeutic efficacy of JAK inhibitors in treating t(8;21) AML. |
| Databáze: | OpenAIRE |
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