Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Leukemia, 2024-05, Vol.38 (5), p.969-980

Ort / Verlag

England: Nature Publishing Group

Erscheinungsjahr

2024

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.