STAT5 is essential for IL-7–mediated viability, growth, and proliferation of T-cell acute lymphoblastic leukemia cells
| Autor: | Ruben van Boxtel, Paul J. Coffer, Bruno A. Cardoso, Alice Melão, Milene Costa da Silva, Daniel Dias Ribeiro, Cristina Santos, Ana Elisa Bauer de Camargo Silva, João T. Barata |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Transcription Genetic Cell Survival T cell T-cell leukemia PIM1 Precursor T-Cell Lymphoblastic Leukemia-Lymphoma 03 medical and health sciences Proto-Oncogene Proteins c-pim-1 Downregulation and upregulation hemic and lymphatic diseases STAT5 Transcription Factor Tumor Cells Cultured medicine Humans Protein kinase B Mechanistic target of rapamycin Cell Proliferation Lymphoid Neoplasia biology Gene Expression Regulation Leukemic Chemistry Interleukin-7 JAK-STAT signaling pathway Hematology medicine.disease Leukemia 030104 developmental biology medicine.anatomical_structure Cancer research biology.protein |
| Zdroj: | Blood Advances Blood Advances, 2(17), 2199. The American Society of Hematology |
| ISSN: | 2473-9537 2473-9529 |
| Popis: | T-cell acute lymphoblastic leukemia (T-ALL) constitutes an aggressive subset of ALL, the most frequent childhood malignancy. Whereas interleukin-7 (IL-7) is essential for normal T-cell development, it can also accelerate T-ALL development in vivo and leukemia cell survival and proliferation by activating phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin signaling. Here, we investigated whether STAT5 could also mediate IL-7 T-ALL-promoting effects. We show that IL-7 induces STAT pathway activation in T-ALL cells and that STAT5 inactivation prevents IL-7-mediated T-ALL cell viability, growth, and proliferation. At the molecular level, STAT5 is required for IL-7-induced downregulation of p27kip1 and upregulation of the transferrin receptor, CD71. Surprisingly, STAT5 inhibition does not significantly affect IL-7-mediated Bcl-2 upregulation, suggesting that, contrary to normal T-cells, STAT5 promotes leukemia cell survival through a Bcl-2-independent mechanism. STAT5 chromatin immunoprecipitation sequencing and RNA sequencing reveal a diverse IL-7-driven STAT5-dependent transcriptional program in T-ALL cells, which includes BCL6 inactivation by alternative transcription and upregulation of the oncogenic serine/threonine kinase PIM1 Pharmacological inhibition of PIM1 abrogates IL-7-mediated proliferation on T-ALL cells, indicating that strategies involving the use of PIM kinase small-molecule inhibitors may have therapeutic potential against a majority of leukemias that rely on IL-7 receptor (IL-7R) signaling. Overall, our results demonstrate that STAT5, in part by upregulating PIM1 activity, plays a major role in mediating the leukemia-promoting effects of IL-7/IL-7R. |
| Databáze: | OpenAIRE |
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