Xbp1s-Negative Tumor B Cells and Pre-Plasmablasts Mediate Therapeutic Proteasome Inhibitor Resistance in Multiple Myeloma

Abstract

SUMMARY Proteasome inhibitor (PI) resistance mechanisms in multiple myeloma (MM) remain controversial. We report the existence of a progenitor organization in primary MM that recapitulates maturation stages between B cells and plasma cells and that contributes to clinical PI resistance. Xbp1s− tumor B cells and pre-plasmablasts survive therapeutic PI, preventing cure, while maturation-arrest of MM before plasmablast stage enables progressive disease on PI treatment. Mechanistically, suppression of Xbp1s in MM is shown to induce bortezomib resistance via de-comittment to plasma cell maturation and immunoglobulin production, diminishing endoplasmic reticulum (ER) front loading and cytotoxic susceptibility to PI-induced inhibition of ER-associated degration (ERAD). These results reveal the tumor progenitor structure in MM and highlight its role in therapeutic failure.

Anti-CD19 CAR T cells with high-dose melphalan and autologous stem cell transplantation for refractory multiple myeloma

“…We therefore suspect that surface immunophenotype is an imperfect predictor of myeloma-propagating potential; rather, the cell-surface immunophenotype of clinically important myeloma-propagating populations likely varies from patient to patient and may even change over time within individual patients during the long natural history of multiple myeloma. From a therapeutic perspective, together with evidence that less mature phenotypes become more frequent with successive lines of therapy (8,52), our results provide rationale to broadly target both B cells and plasma cells to maximize the likelihood of eliminating all aspects of the myeloma clone, both the dominant plasma cell population and minor populations with less mature phenotypes. Indeed, we observed that ex vivo treatment of primary myeloma samples with both CTL019 and anti-BCMA CAR T cells significantly reduced in vitro clonogenicity in all cases examined ( Figure 5).…”

Activation of Liver X Receptors Inhibits Hedgehog Signaling, Clonogenic Growth, and Self-Renewal in Multiple Myeloma

“…T0901317 and 22R also decreased the relative proportion of MM CSCs defined as CD138 neg or ALDH + cells. Since MM CSCs are relatively resistant to several anti-MM agents including the thalidomide analogue lenalidomide and the proteasome inhibitor bortezomib (26, 43), LXR agonists may represent novel strategies to target drug-resistant CSCs.…”

Proteasome inhibitors in cancer therapy

“…In 2013, using RNA-interference screens, Leung-Hagesteijn and colleagues 125 identified that the expression of serine/threonine-protein kinase/endoribonuclease (IRE1) and its downstream transcription factor, effector X-box-binding protein 1 (XBP-1), are required for bortezomib sensitivity. XBP-1 is also a transcription factor involved in plasma-cell differentiation and immunoglobulin production 126 ; these researchers found that, prior to treatment, the myeloma tumour contained subpopulations with different expression levels of IRE1 and XBP-1, which were associated with different sensitivities to bortezomib.…”