Definition of a multiple myeloma progenitor population in mice driven by enforced expression of XBP1s

Multiple myeloma (MM) is an incurable plasma cell malignancy with frequent treatment failures and relapses, suggesting the existence of pathogenic myeloma stem/progenitor populations. However, the identity of MM stem cells remains elusive. We used a murine model of MM with transgenic overexpression of the unfolded protein response sensor X-box binding protein 1 (XBP1s) in the B cell compartment to define MM stem cells. We herein report that a post-germinal center, pre-plasma cell population significantly expands as MM develops. This population has the following characteristics: (a) cell surface phenotype of B220(+)CD19(+)IgM(-)IgD(-)CD138(-)CD80(-)slgG(-)AA4.1(+)FSC(hi); (b) high expression levels of PaxS and Bcl6 with intermediate levels of Blimp1 and XBP1s; (c) increased expression of aldehyde dehydrogenase, Notch1, and c-Kit; and (d) ability to efficiently reconstitute antibody-producing capacity in B cell-deficient mice in vivo. We thus have defined a plasma cell progenitor population that resembles myeloma stem cells in mice. These results provide potentially novel insights into MM stem cell biology and may contribute to the development of novel stem cell-targeted therapies for the eradication of MM.