Abstract
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.
Highlights
These authors contributed : Paolo Sportoletti, Daniele SorciniThese authors jointly supervised this work: Margaret A
The BCL6 co-repressor (BCOR) protein is located in the nucleus [3] where exerts its function as a member of the non-canonical multimeric polycomb group repressive complex 1 (PRC1) which is recruited to the target sites independently of H3K27me3 [4]
Within genes upregulated in both human and mouse cells, there was a striking enrichment of genes regulated by GATA1 (Fig. 6C), suggesting a pivotal role of this transcription factor in driving acute erythroid leukemia (AEL). These findings provided evidence that our AEL mouse may serve as an operational platform for human Bcor-flox/floxCre + (Bcor−/−)Dnmt3a−/− leukemia modeling
Summary
These authors jointly supervised this work: Margaret A. The BCOR protein is located in the nucleus [3] where exerts its function as a member of the non-canonical multimeric polycomb group repressive complex 1 (PRC1) which is recruited to the target sites independently of H3K27me3 [4] This complex is involved in the control of various biological processes, including pluripotency, reprogramming, and hematopoiesis [4, 5]. The Bcor−/−Dnmt3a−/− double knockout mice developed a fully penetrant acute erythroid leukemia (AEL) sensitive to demethylating agents Information gained from this model expand our knowledge on the biology of AEL and may help to design new rational treatments for patients suffering from this high-risk leukemia
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