The Eμ-Ret mouse is a novel model of hyperdiploid B-cell acute lymphoblastic leukemia

The Eμ-Ret mouse is a novel model of hyperdiploid B-cell acute lymphoblastic leukemia

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 appropr...

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Bibliographic Details
Published in:Leukemia Vol. 38; no. 5; pp. 969 - 980
Main Authors: Farrokhi, Ali, Atre, Tanmaya, Rever, Jenna, Fidanza, Mario, Duey, Wendy, Salitra, Samuel, Myung, Junia, Guo, Meiyun, Jo, Sumin, Uzozie, Anuli, Baharvand, Fatemeh, Rolf, Nina, Auer, Franziska, Hauer, Julia, Grupp, Stephan A., Eydoux, Patrice, Lange, Philipp F., Seif, Alix E., Maxwell, Christopher A., Reid, Gregor S. D.
Format: Journal Article
Language:English
Published: London Nature Publishing Group UK 01-05-2024
Nature Publishing Group
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Abnormalities
Acute lymphoblastic leukemia
Aneuploidy
Animals
Cancer Research
Centrosome - pathology
Centrosomes
Chromosomes
Clustering
Critical Care Medicine
Diploidy
Disease Models, Animal
Gene expression
Hematology
Humans
Immune system
In vivo methods and tests
Intensive
Internal Medicine
Latency
Leukemia
Leukemogenesis
Lymphatic leukemia
Lymphocytes B
Medicine
Medicine & Public Health
Mice
Myelodysplastic syndrome
Oncology
Pediatrics
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - genetics
Precursor B-Cell Lymphoblastic Leukemia-Lymphoma - pathology
Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics
Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology
Supernumerary
Supernumerary chromosomes
Trisomy
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Summary: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 Eμ-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 Eμ-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 Eμ-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.
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ISSN:0887-6924
1476-5551
DOI:10.1038/s41375-024-02221-x