Frequent loss of RAF kinase inhibitor protein expression in acute myeloid leukemia
| Autor: | David Matallanas, Albert Wölfler, Claudia Bodner, Franz Quehenberger, Daniela Pirkebner, Heinz Sill, Armin Zebisch, O Wolf, Astrid Drasche, Jakob Troppmair, Karin Lind, Ruud Delwel, Martina Haller, Karen Blyth, Isabella Fried, Erdogan Taskesen, Oliver Rath, Walter Kolch |
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| Přispěvatelé: | Hematology |
| Rok vydání: | 2012 |
| Předmět: |
Cancer Research
Myeloid CD34 Phosphatidylethanolamine Binding Protein Biology Monocytes Western blot acute myeloid leukemia (AML) hemic and lymphatic diseases Cell Line Tumor medicine Humans Myeloid Cells Progenitor cell Protein kinase A Cell Proliferation medicine.diagnostic_test Gene Expression Regulation Leukemic Myeloid leukemia RAF kinase inhibitor protein (RKIP) Cell Differentiation Hematology Prognosis Cell biology Haematopoiesis Leukemia Myeloid Acute medicine.anatomical_structure Cell Transformation Neoplastic Genes ras Oncology Cell culture Mutation Cancer research |
| Zdroj: | Leukemia, 26(8), 1842-1849. Nature Publishing Group |
| ISSN: | 1476-5551 0887-6924 |
| Popis: | RAF kinase inhibitor protein (RKIP) is a negative regulator of the RAS-mitogen-activated protein kinase/extracellular signal-regulated kinase signaling cascade. We investigated its role in acute myeloid leukemia (AML), an aggressive malignancy arising from hematopoietic stem and progenitor cells (HSPCs). Western blot analysis revealed loss of RKIP expression in 19/103 (18%) primary AML samples and 4/17 (24%) AML cell lines but not in 10 CD34+ HSPC specimens. In in-vitro experiments with myeloid cell lines, RKIP overexpression inhibited cellular proliferation and colony formation in soft agar. Analysis of two cohorts with 103 and 285 AML patients, respectively, established a correlation of decreased RKIP expression with monocytic phenotypes. RKIP loss was associated with RAS mutations and in transformation assays, RKIP decreased the oncogenic potential of mutant RAS. Loss of RKIP further related to a significantly longer relapse-free survival and overall survival in uni- and multivariate analyses. Our data show that RKIP is frequently lost in AML and correlates with monocytic phenotypes and mutations in RAS. RKIP inhibits proliferation and transformation of myeloid cells and decreases transformation induced by mutant RAS. Finally, loss of RKIP seems to be a favorable prognostic parameter in patients with AML. Deposited by bulk import |
| Databáze: | OpenAIRE |
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