EMD originates from hyaluronan-induced homophilic interactions of CD44 variant-expressing MM cells under shear stress

Extramedullary disease (EMD) is known to be associated with chemoresistance and poor prognosis in multiple myeloma (MM); however, the mechanisms of its development are not fully understood. Elucidating the mechanism of EMD development and its therapeutic targeting would greatly contribute to further improvement of treatment outcome in patients with MM. Here, we show that bone marrow stroma cell-derived hyaluronan (HA) elicits homophilic interactions of MM cells by binding to surface CD44, especially long-stretch variants, under physiological shear stress and generates cell clusters that might develop into EMD. We recapitulated the development of EMD via administration of HA in a syngeneic murine MM model in a CD44-dependent manner. HA-induced MM cell clusters exhibited the specific resistance to proteasome inhibitors (PIs) in vitro and in murine models via gamma-secretase-mediated cleavage of the intracellular domains of CD44, which in turn transactivated PI resistance-inducible genes. Treatment of HA-injected mice with anti-CD44 antibody or gamma-secretase inhibitors readily suppressed the development of EMD from transplanted MM cells and significantly prolonged the survival of recipients by overcoming PI resistance. The HA-CD44 axis represents a novel pathway to trigger EMD development and could be a target of the prediction, prevention, and treatment of EMD in patients with MM.

Automated summary

Extramedullary disease (EMD) in multiple myeloma (MM) is associated with resistance to chemotherapy and poor prognosis, and its development mechanisms are not fully understood. This study demonstrates that bone marrow stroma cell-derived hyaluronan (HA) binds to surface CD44 on MM cells, leading to the formation of cell clusters that could develop into EMD. These HA-induced cell clusters exhibit resistance to proteasome inhibitors (PIs) through gamma-secretase-mediated cleavage of CD44, and targeting the HA-CD44 axis effectively suppresses EMD development and overcomes PI resistance.