Distinct classes of c-Kit–activating mutations differ in their ability to promote RUNX1-ETO–associated acute myeloid leukemia
| Autor: | Christopher A. Klug, Hyung-Gyoon Kim, Kevin W. Harris, Heidi J. Nick, Vishnu Reddy, Chia-Wei Chang |
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| Rok vydání: | 2012 |
| Předmět: |
Oncogene Proteins
Fusion Blotting Western Immunology Bone Marrow Cells Biology medicine.disease_cause Biochemistry Receptor tyrosine kinase Mice chemistry.chemical_compound RUNX1 Translocation Partner 1 Protein Transduction Genetic hemic and lymphatic diseases medicine Animals Humans Myeloid Cells Cells Cultured Mutation Myeloid Neoplasia Hematopoietic Stem Cell Transplantation Myeloid leukemia Cell Biology Hematology Flow Cytometry Hematopoietic Stem Cells medicine.disease Molecular biology Mice Inbred C57BL Transplantation Proto-Oncogene Proteins c-kit Leukemia Haematopoiesis Retroviridae RUNX1 chemistry Leukemia Myeloid Acute Disease Core Binding Factor Alpha 2 Subunit NIH 3T3 Cells biology.protein Tyrosine kinase |
| Zdroj: | Blood. 119:1522-1531 |
| ISSN: | 1528-0020 0006-4971 |
| Popis: | The t(8;21) RUNX1-ETO translocation is one of the most frequent cytogenetic abnormalities in acute myeloid leukemia (AML). In RUNX1-ETO+ patient samples, differing classes of activating c-KIT receptor tyrosine kinase mutations have been observed. The most common (12%-48%) involves mutations, such as D816V, which occur in the tyrosine kinase domain, whereas another involves mutations within exon 8 in a region mediating receptor dimerization (2%-13% of cases). To test whether distinct subtypes of activating c-KIT mutations differ in their leukemogenic potential in association with RUNX1-ETO, we used a retroviral transduction/transplantation model to coexpress RUNX1-ETO with either c-KitD814V or c-KitT417IΔ418-419 in murine hematopoietic stem/progenitor cells used to reconstitute lethally irradiated mice. Analysis of reconstituted animals showed that RUNX1-ETO;c-KitD814V coexpression resulted in 3 nonoverlapping phenotypes. In 45% of animals, a transplantable AML of relatively short latency and frequent granulocytic sarcoma was noted. Other mice exhibited a rapidly fatal myeloproliferative phenotype (35%) or a lethal, short-latency pre-B-cell leukemia (20%). In contrast, RUNX1-ETO;c-KitT417IΔ418-419 coexpression promoted exclusively AML in a fraction (51%) of reconstituted mice. These observations indicate that c-KitD814V promotes a more varied and aggressive leukemic phenotype than c-KitT417IΔ418-419, which may be the result of differing potencies of the activating c-Kit alleles. |
| Databáze: | OpenAIRE |
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