期刊
LEUKEMIA
卷 35, 期 7, 页码 1949-1963出版社
SPRINGERNATURE
DOI: 10.1038/s41375-020-01075-3
关键词
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资金
- Italian Association for Cancer Research (AIRC) [23604]
- Fondation ARC (Leopold Griffuel Award)
- Edward P. Evans Foundation
- National Institutes of Health [DK092883, CA183252, AG036695, CA125123]
- Howard Hughes Medical Institute
Recurrent loss-of-function mutations of the BCOR gene are associated with poor prognosis in AML patients, leading to the creation of a mouse model to study this AML genotype. Double knockout mice showed features of acute erythroid leukemia, suggesting potential efficacy of demethylating agents in AEL treatment.
Recurrent loss-of-function mutations of BCL6 co-repressor (BCOR) gene are found in about 4% of AML patients with normal karyotype and are associated with DNMT3a mutations and poor prognosis. Therefore, new anti-leukemia treatments and mouse models are needed for this combinatorial AML genotype. For this purpose, we first generated a Bcor(-/-) knockout mouse model characterized by impaired erythroid development (macrocytosis and anemia) and enhanced thrombopoiesis, which are both features of myelodysplasia/myeloproliferative neoplasms. We then created and characterized double Bcor(-/-)/Dnmt3a(-/-) knockout mice. Interestingly, these animals developed a fully penetrant acute erythroid leukemia (AEL) characterized by leukocytosis secondary to the expansion of blasts expressing c-Kit+ and the erythroid marker Ter119, macrocytic anemia and progressive reduction of the thrombocytosis associated with loss of Bcor alone. Transcriptomic analysis of double knockout bone marrow progenitors revealed that aberrant erythroid skewing was induced by epigenetic changes affecting specific transcriptional factors (GATA1-2) and cell-cycle regulators (Mdm2, Tp53). These findings prompted us to investigate the efficacy of demethylating agents in AEL, with significant impact on progressive leukemic burden and mice overall survival. Information gained from our model expands the knowledge on the biology of AEL and may help designing new rational treatments for patients suffering from this high-risk leukemia.
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