Multiple myeloma (MM) is a fatal neoplastic disease of B-cell origin and is the most common cancer of the skeleton. Bone marrow stromal cells (BMSC) play a critical role in supporting MM cell growth and bone destruction by producing growth factors and inflammatory cytokines. Human X-box binding protein-1 spliced (hXBP1s) is a stromal-intrinsic oncogenic factor that plays an essential role in regulating stromal support of MM. Overexpression of hXBP1s in B-cells leads to the malignant transformation of B-cells to multiple myeloma tumor cells. The hXBP1s protein is highly expressed in both MM cells and BMSC derived from MM patients. The hXBP1 protein is a direct and physiological substrate of c-Jun N-terminal kinases (JNKs), which are activated in many widely-used therapeutic agents for MM, and which phosphorylate hXBP1s at serine 288 (Ser288). The de-phosphorylation of hXBP1s at Ser288 enhances BMSC support of MM cell growth and osteoclast formation both in vitro and in vivo, indicating that phosphorylation of hXBP1s by JNKs is required to produce an inhibitory effect on BMSC support of MM cell growth. The phosphorylation level of hXBP1s correlates with a favorable clinical response to such therapeutic agents, while induction of JNK activity in MM cells leads to apoptosis, contributing to the therapeutic effects of JNK-activating agents on MM.
Histopathological image of multiple myeloma.
Description
Researchers have developed a novel method for monitoring effectiveness of multiple myeloma therapies which activate JNK kinase activity. Taken together, the phosphorylation of hXBP1s and JNK-induced cell death reveal that the JNKs-mediated phosphorylation of hXBP1s is a novel molecular mechanism in regulating hXBP1s protein stability and mediating the therapeutic effects of JNKs-activating MM drugs on the MM bone microenvironment. Thus, Ser288 phosphorylation of hXBP1s may serve as a valid biomarker for predicting the therapeutic outcomes and drug sensitivity of MM patients in response to JNKs-activating drugs. In addition, the inventors have demonstrated that the triplet drug combination of dexamethasone, bortezomib, and thalidomide, increases the amount of hXBP1 phosphorylated at Ser288 in bone marrow of MM patients. By measuring and comparing the Ser288-mediated hXBP1 phosphorylation in MM bone marrow tissue using a custom-made antibody designed to recognize Ser288, researchers can monitor effectiveness of different MM therapies, help clinicians optimize personal treatment strategies, and develop new treatments.
Applications
· Monitoring responsiveness and effectiveness of different MM therapies in which the JNK/XPB1 interaction plays a role.
· Helping clinicians make informed decision on optimal personalized treatment strategies for MM patients.
Advantages
. By measuring and comparing the Ser288-mediated hXBP1 phosphorylation in MM bone marrow tissue using a custom-made antibody designed to recognize Ser288, researchers can monitor effectiveness of different MM therapies, help clinicians optimize personal treatment strategies, and develop new treatments.
Invention Readiness
Prototype
IP Status
https://patents.google.com/patent/US11137400B2Related Publication(s)
Xu, G., Liu, K., Anderson, J., Patrene, K., Lentzsch, S., Roodman, G. D., & Ouyang, H. (2012). Expression of XBP1s in bone marrow stromal cells is critical for myeloma cell growth and osteoclast formation. Blood, 119(18), 4205–4214. https://doi.org/10.1182/blood-2011-05-353300
