The Potential of JAG Ligands as Therapeutic Targets and Predictive Biomarkers in Multiple Myeloma

The NOTCH ligands JAG1 and JAG2 have been correlated in vitro with multiple myeloma
(MM) cell proliferation, drug resistance, self-renewal and a pathological crosstalk with the tumor
microenvironment resulting in angiogenesis and osteoclastogenesis. These findings suggest that a
therapeutic approach targeting JAG ligands might be helpful for the care of MM patients and lead us
to explore the role of JAG1 and JAG2 in a MM in vivo model and primary patient samples. JAG1 and
JAG2 protein expression represents a common feature in MM cell lines; therefore, we assessed their
function through JAG1/2 conditional silencing in a MM xenograft model. We observed that JAG1
and JAG2 showed potential as therapeutic targets in MM, as their silencing resulted in a reduction
in the tumor burden. Moreover, JAG1 and JAG2 protein expression in MM patients was positively
correlated with the presence of MM cells in patients’ bone marrow biopsies. Finally, taking advantage
of the Multiple Myeloma Research Foundation (MMRF) CoMMpass global dataset, we showed that
JAG2 gene expression level was a predictive biomarker associated with patients’ overall survival
and progression-free survival, independently from other main molecular or clinical features. Overall,
these results strengthened the rationale for the development of a JAG1/2-tailored approach and the
use of JAG2 as a predictive biomarker in MM.