PIM inhibitors target CD25-positive AML cells through concomitant suppression of STAT5 activation and degradation of MYC oncogene
| Autor: | Fangxian Sun, Laurent Schio, Carlos Garcia-Echeverria, Dietmar Hoffmann, Shih Min A Huang, Christoph Lengauer, Bailin Zhang, Vinod F. Patel, Francisco Adrian, Michel Tabart, Hong Cheng, Weidong Zhang, Anlai Wang, Qiang Gao, Zhuyan Guo, Jingxin Zhang, Claude Barberis, Stefan Gross, Josh Murtie, Jennifer Rocnik, Mikhail Levit, Dmitri Wiederschain, Marion Dorsch |
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| Rok vydání: | 2014 |
| Předmět: |
Male
Myeloid Immunology Antineoplastic Agents HL-60 Cells Biology Biochemistry Proto-Oncogene Proteins c-myc Proto-Oncogene Proteins c-pim-1 hemic and lymphatic diseases STAT5 Transcription Factor medicine Humans IL-2 receptor Oncogene Gene Expression Regulation Leukemic Interleukin-2 Receptor alpha Subunit Cancer Myeloid leukemia Cell Biology Hematology medicine.disease Leukemia Myeloid Acute Leukemia medicine.anatomical_structure Proteolysis Cancer cell Cancer research Female Blast Crisis Tyrosine kinase |
| Zdroj: | Blood. 124:1777-1789 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2014-01-551234 |
| Popis: | Postchemotherapy relapse presents a major unmet medical need in acute myeloid leukemia (AML), where treatment options are limited. CD25 is a leukemic stem cell marker and a conspicuous prognostic marker for overall/relapse-free survival in AML. Rare occurrence of genetic alterations among PIM family members imposes a substantial hurdle in formulating a compelling patient stratification strategy for the clinical development of selective PIM inhibitors in cancer. Here we show that CD25, a bona fide STAT5 regulated gene, is a mechanistically relevant predictive biomarker for sensitivity to PIM kinase inhibitors. Alone or in combination with tyrosine kinase inhibitors, PIM inhibitors can suppress STAT5 activation and significantly shorten the half-life of MYC to achieve substantial growth inhibition of high CD25-expressing AML cells. Our results highlight the importance of STAT5 and MYC in rendering cancer cells sensitive to PIM inhibitors. Because the presence of a CD25-positive subpopulation in leukemic blasts correlates with poor overall or relapse-free survival, our data suggest that a combination of PIM inhibitors with chemotherapy and tyrosine kinase inhibitors could improve long-term therapeutic outcomes in CD25-positive AML. |
| Databáze: | OpenAIRE |
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