Expression of NrasQ61R and MYC transgene in germinal center B cells induces a highly malignant multiple myeloma in mice. Blood 2021 Jan 07;137(1):61-74
Date
07/09/2020Pubmed ID
32640012Pubmed Central ID
PMC7808014DOI
10.1182/blood.2020007156Scopus ID
2-s2.0-85099107626 (requires institutional sign-in at Scopus site) 16 CitationsAbstract
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.
Author List
Wen Z, Rajagopalan A, Flietner ED, Yun G, Chesi M, Furumo Q, Burns RT, Papadas A, Ranheim EA, Pagenkopf AC, Morrow ZT, Finn R, Zhou Y, Li S, You X, Jensen J, Yu M, Cicala A, Menting J, Mitsiades CS, Callander NS, Bergsagel PL, Wang D, Asimakopoulos F, Zhang JAuthor
Demin Wang PhD Professor in the Microbiology and Immunology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsB-Lymphocytes
Disease Models, Animal
Germinal Center
Mice
Mice, Inbred C57BL
Mice, Transgenic
Monomeric GTP-Binding Proteins
Multiple Myeloma
Proto-Oncogene Proteins c-myc
Transgenes