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

Author

Listed:
  • Francesco Maura

    (University of Miami)

  • David G. Coffey

    (University of Miami)

  • Caleb K. Stein

    (Mayo Clinic)

  • Esteban Braggio

    (Mayo Clinic)

  • Bachisio Ziccheddu

    (University of Miami)

  • Meaghen E. Sharik

    (Mayo Clinic)

  • Megan T. Du

    (Mayo Clinic)

  • Yuliza Tafoya Alvarado

    (Mayo Clinic)

  • Chang-Xin Shi

    (Mayo Clinic)

  • Yuan Xiao Zhu

    (Mayo Clinic)

  • Erin W. Meermeier

    (Mayo Clinic)

  • Gareth J. Morgan

    (NYU Langone, Perlmutter Cancer Center)

  • Ola Landgren

    (University of Miami)

  • P. Leif Bergsagel

    (Mayo Clinic)

  • Marta Chesi

    (Mayo Clinic)

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.

Suggested Citation

  • 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, 2024. "The genomic landscape of Vk*MYC myeloma highlights shared pathways of transformation between mice and humans," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48091-w
    DOI: 10.1038/s41467-024-48091-w
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    References listed on IDEAS

    as
    1. Francesco Maura & Andrea Degasperi & Ferran Nadeu & Daniel Leongamornlert & Helen Davies & Luiza Moore & Romina Royo & Bachisio Ziccheddu & Xose S. Puente & Herve Avet-Loiseau & Peter J. Campbell & Se, 2019. "Author Correction: A practical guide for mutational signature analysis in hematological malignancies," Nature Communications, Nature, vol. 10(1), pages 1-1, December.
    2. Francesco Maura & Andrea Degasperi & Ferran Nadeu & Daniel Leongamornlert & Helen Davies & Luiza Moore & Romina Royo & Bachisio Ziccheddu & Xose S. Puente & Herve Avet-Loiseau & Peter J. Campbell & Se, 2019. "A practical guide for mutational signature analysis in hematological malignancies," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
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