Expression of NrasQ61R and MYC transgene in germinal center B cells induces a highly malignant multiple myeloma in mice

Zhi Wen, Adhithi Rajagopalan, Evan D. Flietner, Grant Yun, Marta Chesi, Quinlan Furumo, Robert T. Burns, Athanasios Papadas, Erik A. Ranheim, Adam C. Pagenkopf, Zachary T. Morrow, Remington Finn, Yun Zhou, Shuyi Li, Xiaona You, Jeffrey Jensen, Mei Yu, Alexander Cicala, James Menting, Constantine S. MitsiadesNatalie S. Callander, P. Leif Bergsagel, Demin Wang, Fotis Asimakopoulos, Jing Zhang

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

NRAS Q61 mutations are prevalent in advanced/relapsed multiple myeloma (MM) and correlate with poor patient outcomes. Thus, we generated a novel MM model by conditionally activating expression of endogenous NrasQ61R and an MYC transgene in germinal center (GC) B cells (VQ mice). VQ mice developed a highly malignant MM characterized by a high proliferation index, hyperactivation of extracellular signal-regulated kinase and AKT signaling, impaired hematopoiesis, widespread extramedullary disease, bone lesions, kidney abnormalities, preserved programmed cell death protein 1 and T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domain immune-checkpoint pathways, and expression of human high-risk MM gene signatures. VQ MM mice recapitulate most of the biological and clinical features of human advanced/ high-risk MM. These MM phenotypes are serially transplantable in syngeneic recipients. Two MM cell lines were also derived to facilitate future genetic manipulations. Combination therapies based on MEK inhibition significantly prolonged the survival of VQ mice with advanced-stage MM. Our study provides a strong rationale to develop MEK inhibition-based therapies for treating advanced/relapsed MM.

Original languageEnglish (US)
Pages (from-to)61-74
Number of pages14
JournalBlood
Volume137
Issue number1
DOIs
StatePublished - Jan 7 2021

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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