The genomic landscape of Vk*MYC myeloma highlights shared pathways of transformation between mice and humans
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, Marta Chesi
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.