1. The genomic landscape of Vk*MYC myeloma highlights shared pathways of transformation between mice and humans
- Author
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Francesco Maura, David G. Coffey, Caleb K. Stein, Esteban Braggio, Bachisio Ziccheddu, Meaghen E. Sharik, Megan T. Du, Yuliza Tafoya Alvarado, Chang-Xin Shi, Yuan Xiao Zhu, Erin W. Meermeier, Gareth J. Morgan, Ola Landgren, P. Leif Bergsagel, and Marta Chesi
- Subjects
Science - Abstract
Abstract Multiple myeloma (MM) is a heterogeneous disease characterized by frequent MYC translocations. Sporadic MYC activation in the germinal center of genetically engineered Vk*MYC mice is sufficient to induce plasma cell tumors in which a variety of secondary mutations are spontaneously acquired and selected over time. Analysis of 119 Vk*MYC myeloma reveals recurrent copy number alterations, structural variations, chromothripsis, driver mutations, apolipoprotein B mRNA-editing enzyme, catalytic polypeptide (APOBEC) mutational activity, and a progressive decrease in immunoglobulin transcription that inversely correlates with proliferation. Moreover, we identify frequent insertional mutagenesis by endogenous retro-elements as a murine specific mechanism to activate NF-kB and IL6 signaling pathways shared with human MM. Despite the increased genomic complexity associated with progression, advanced tumors remain dependent on MYC. In summary, here we credential the Vk*MYC mouse as a unique resource to explore MM genomic evolution and describe a fully annotated collection of diverse and immortalized murine MM tumors.
- Published
- 2024
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