TY - JOUR
T1 - Expression of NrasQ61R and MYC transgene in germinal center B cells induces a highly malignant multiple myeloma in mice
AU - Wen, Zhi
AU - Rajagopalan, Adhithi
AU - Flietner, Evan D.
AU - Yun, Grant
AU - Chesi, Marta
AU - Furumo, Quinlan
AU - Burns, Robert T.
AU - Papadas, Athanasios
AU - Ranheim, Erik A.
AU - Pagenkopf, Adam C.
AU - Morrow, Zachary T.
AU - Finn, Remington
AU - Zhou, Yun
AU - Li, Shuyi
AU - You, Xiaona
AU - Jensen, Jeffrey
AU - Yu, Mei
AU - Cicala, Alexander
AU - Menting, James
AU - Mitsiades, Constantine S.
AU - Callander, Natalie S.
AU - Leif Bergsagel, P.
AU - Wang, Demin
AU - Asimakopoulos, Fotis
AU - Zhang, Jing
N1 - Publisher Copyright:
© 2021 American Society of Hematology. All rights reserved.
PY - 2021/1/7
Y1 - 2021/1/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85099107626&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85099107626&partnerID=8YFLogxK
U2 - 10.1182/blood.2020007156
DO - 10.1182/blood.2020007156
M3 - Article
C2 - 32640012
AN - SCOPUS:85099107626
SN - 0006-4971
VL - 137
SP - 61
EP - 74
JO - Blood
JF - Blood
IS - 1
ER -