PML/RARα and FLT3-ITD induce an APL-like disease in a mouse model
| Autor: | Jeffrey L. Kutok, Ifor R. Williams, Christina L. Boulton, Timothy J. Ley, D. Gary Gilliland, Louise M Kelly, Sonia M Amaral, David P. Curley |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2002 |
| Předmět: |
Acute promyelocytic leukemia
Cathepsin G Oncogene Proteins Fusion Mice Inbred Strains Mice Transgenic Tretinoin medicine.disease_cause Immunophenotyping Promyelocytic leukemia protein Mice Leukemia Promyelocytic Acute immune system diseases hemic and lymphatic diseases medicine Animals Humans neoplasms Crosses Genetic Tumor Stem Cell Assay Mutation Mice Inbred C3H Multidisciplinary biology Serine Endopeptidases Membrane Proteins Biological Sciences medicine.disease Fusion protein Virology Cathepsins Neoplasm Proteins Retinoic acid receptor Leukemia Cancer research biology.protein Neoplasm Transplantation medicine.drug |
| Popis: | Acute promyelocytic leukemia (APL) cells invariably express aberrant fusion proteins involving the retinoic acid receptor α (RARα). The most common fusion partner is promyelocytic leukemia protein (PML), which is fused to RARα in the balanced reciprocal chromosomal translocation, t(15;17)(q22:q11). Expression of PML/RARα from the cathepsin G promoter in transgenic mice causes a nonfatal myeloproliferative syndrome in all mice; about 15% go on to develop APL after a long latent period, suggesting that additional mutations are required for the development of APL. A candidate target gene for a second mutation is FLT3 , because it is mutated in approximately 40% of human APL cases. Activating mutations in FLT3, including internal tandem duplication (ITD) in the juxtamembrane domain, transform hematopoietic cell lines to factor independent growth. FLT3-ITDs also induce a myeloproliferative disease in a murine bone marrow transplant model, but are not sufficient to cause AML. Here, we test the hypothesis that PML/RARα can cooperate with FLT3-ITD to induce an APL-like disease in the mouse. Retroviral transduction of FLT3-ITD into bone marrow cells obtained from PML/RARα transgenic mice results in a short latency APL-like disease with complete penetrance. This disease resembles the APL-like disease that occurs with long latency in the PML/RARα transgenics, suggesting that activating mutations in FLT3 can functionally substitute for the additional mutations that occur during mouse APL progression. The leukemia is transplantable to secondary recipients and is ATRA responsive. These observations document cooperation between PML/RARα and FLT3-ITD in development of the murine APL phenotype. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|