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Mouse models of human multiple myeloma subgroups.

Wiebke Winkler1,2,3,4, Carlota Farré Díaz1,2,3,4, Eric Blanc5

  • 1Immune Regulation and Cancer, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Berlin 13125, Germany.

Proceedings of the National Academy of Sciences of the United States of America
|February 28, 2023
PubMed
Summary

Researchers created new mouse models for multiple myeloma (MM) by targeting specific genes in B cells. These models accurately mimic distinct human MM subtypes, aiding in understanding disease development and treatment.

Keywords:
Cyclin D1/MMSETchromosomal translocationsconditional mouse modelsmultiple myelomatranslocation subgroups

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Area of Science:

  • Hematology
  • Oncology
  • Genetics

Background:

  • Multiple myeloma (MM) is a cancer originating from plasma cells, with distinct genetic subtypes like t(11;14)/CCND1 and t(4;14)/MMSET.
  • Secondary NF-κB activation is common in human MM, suggesting its role in pathogenesis.

Purpose of the Study:

  • To generate genetically defined, subgroup-specific mouse models of multiple myeloma.
  • To investigate the role of specific genetic translocations in MM development and characteristics.

Main Methods:

  • Coactivation of mouse Ccnd1 or MMSET with a constitutively active Ikk2 mutant in germinal center (GC) B cells.
  • Development and characterization of genetically engineered mouse models (GEMMs).

Main Results:

  • Ccnd1/Ikk2ca and MMSET/Ikk2ca mice developed age-dependent plasma cell outgrowth, mimicking MM features like M spikes, bone marrow insufficiency, and bone lesions.
  • Transgenic plasma cells exhibited distinct transcriptional profiles similar to human MM counterparts.
  • The generated models recapitulated key features of human MM subgroups.

Conclusions:

  • Targeting genes involved in MM-specific translocations in mouse GC B cells creates distinct, human MM-like diseases.
  • These models provide valuable tools for studying the pathogenesis and therapeutic vulnerabilities of different MM subtypes.