| First Author | Farrokhi A | Year | 2024 |
| Journal | Leukemia | Volume | 38 |
| Issue | 5 | Pages | 969-980 |
| PubMed ID | 38519798 | Mgi Jnum | J:352282 |
| Mgi Id | MGI:7705800 | Doi | 10.1038/s41375-024-02221-x |
| Citation | Farrokhi A, et al. (2024) The Emu-Ret mouse is a novel model of hyperdiploid B-cell acute lymphoblastic leukemia. Leukemia 38(5):969-980 |
| abstractText | The presence of supernumerary chromosomes is the only abnormality shared by all patients diagnosed with high-hyperdiploid B cell acute lymphoblastic leukemia (HD-ALL). Despite being the most frequently diagnosed pediatric leukemia, the lack of clonal molecular lesions and complete absence of appropriate experimental models have impeded the elucidation of HD-ALL leukemogenesis. Here, we report that for 23 leukemia samples isolated from moribund Emu-Ret mice, all were characterized by non-random chromosomal gains, involving combinations of trisomy 9, 12, 14, 15, and 17. With a median gain of three chromosomes, leukemia emerged after a prolonged latency from a preleukemic B cell precursor cell population displaying more diverse aneuploidy. Transition from preleukemia to overt disease in Emu-Ret mice is associated with acquisition of heterogeneous genomic abnormalities affecting the expression of genes implicated in pediatric B-ALL. The development of abnormal centrosomes in parallel with aneuploidy renders both preleukemic and leukemic cells sensitive to inhibitors of centrosome clustering, enabling targeted in vivo depletion of leukemia-propagating cells. This study reveals the Emu-Ret mouse to be a novel tool for investigating HD-ALL leukemogenesis, including supervision and selection of preleukemic aneuploid clones by the immune system and identification of vulnerabilities that could be targeted to prevent relapse. |
