July-August 2019, Volume 16, Issue 4
XBP1s: Getting to the Roots of Multiple Myeloma
Published on: June 03, 2019
Kellner J, Wallace C, Liu B, et al. Definition of a multiple myeloma progenitor in mice driven by enforced expression of XBP1s. JCI Insight. 2019;4:e124698.
Multiple myeloma (MM) is a hematologic cancer characterized by the accumulation of malignant clonal plasma cells in the bone marrow (BM), resulting in the secretion of monoclonal immunoglobulins. Despite the improvement in biological understanding and development of novel therapeutics, MM remains an incurable disease.1
Most end-stage myeloma cells are short-lived, terminally differentiated plasma B cells. Therefore, as is the case for many clonal tumors, cancer stem cells (CSCs) or in this case MM stem cells (MMSCs) are thought to be the cause of disease recurrence and progression. Although the concept of CSC has been around for decades, CSCs were only definitely described in 1997 in acute myeloid leukemia.2 Since that time, this population has been identified in many solid and hematologic tumors including MM. Several markers have been used to identify MMSCs, including side population and aldehyde dehydrogenase (ALDH) activity. Side population cells were first identified in murine BM with the ability to efflux the fluorescent dye Hoechst 33342. They share CSC properties such as tumorigenic potential, expression of stem-like genes, and resistance to chemotherapeutic drugs.3 Conversely, ALDH has been reported to be highly expressed in primitive hematopoietic stem cells and shows increased activity in CSCs purified from various solid and hematopoietic cancers.4 However, the identification of MMSCs should rely on phenotype rather than CSC characteristics. In that regard, an MMSC can be defined as a cell in the malignant tissue that can self-renew and differentiate into predominantly myeloma clones that constitute the lesion. Conceptually, a proper CSC assay should evaluate whether a population can propagate malignant clones indefinitely and produce overt disease in an in vivo setting.5 However, most prior studies on MMSCs were done either in an in vitro clonogenic assay cocultured with stromal cells or in a xenograft setting without an intact host immune system.
In their article, Dr. Joshua Kellner and colleagues described the first study identifying a progenitor population of myeloma cells, using a murine model of MM with B cell–specific overexpression of the unfolded protein response sensor X-box binding protein 1 (XBP1). XBP1 plays critical roles in the differentiation of B cells into plasma cells (PC) and in the maintenance of PC functions. It has been shown to be upregulated in myeloma cells and serves as a biomarker for progression from premalignancy monoclonal gammopathy of undetermined significance (MGUS) to overt MM. Although this XBP1 transgenic (XBP1s-Tg) mouse has been reported previously as a recapitulation of the clinical development of MGUS to MM, no detailed analysis of the B-cell compartment has been performed. In this study, Dr. Kellner and colleagues investigated the kinetics of B-cell development in XBP1-Tg mice and found MM plasma progenitor (MMPPs) that are post–germinal center, class-switched B cells (B220+CD19+IgM-IgD-), transitional preplasmablasts (CD80+), and preplasma cells (CD138-). Based on surface IgG (sIgG), AA4.1/CD93 expression, and granularity, these MMPPs can be further divided into PC progenitor cells (PCPCs; sIgG-AA4.1+FSChi) and B-cell progenitor cells (BCPCs; sIgG-AA4.1+FSClo). The authors then comprehensively examined these two progenitor cells on the expression of critical transcription factors, expression of adhesion molecules, antigen specificity, morphology, stem/progenitor–like characteristics, and ability to differentiate to myeloma cells in vivo.
As expected, BCPCs express high levels of Pax5, a transcription factor important for maintaining B cell phenotype and preventing plasma B cell formation. Similarly, PCs express high levels of Bcl6 and Blimp1, which are critical for functions of post–germinal center B cells and PC, respectively. Interestingly, PCPCs express high levels of both Pax5 and Bcl6, but only intermediate levels of Blimp1, suggesting a transitional state between BCPC and PC. The authors then used human serum albumin (HSA) immunization to examine antigen specificity of these subpopulations. HSA-specific memory B cell, a positive control, captured both high levels of total and surface HSA, while PCs captured high levels of total HSA but low surface antigen binding due to Ig downregulation. Interestingly, PCPCs exhibited a high total HSA reactivity yet maintained high surface HSA binding, further suggesting that PCPCs represent an intermediate population between memory B cells and PCs that haven’t yet downregulated surface Igs. Additionally, PCPCs possess characteristics of stem/progenitor population such as high ALDH activity, and high Notch1 and c-Kit expression, while morphologically resembling a B cell transitioning to PCl. When transplanted into syngeneic B-cell deficient mice, PCPCs rather than PC or BCPC generated high levels of IgG1 and IgM antibodies, resembling overt myeloma disease.
In this study, using a B cell–specific XBP-1 transgenic murine model, Dr. Kellner and colleagues have defined a PCPC population as B220+CD19+IgM-IgD-CD138-CD80+sIgG-AA4.1+FSChi. This is the first study to identify a myeloma progenitor population that can lead to overt myeloma disease in an immune-competent in vivo system. These PCPCs possess CSC-like characteristics such as high ALDH activity and BrdU retention, suggesting a potential MM CSC. Despite the lasting assumption that MM CSC may come from a late–B cell and pre-PC population, this is the first report to provide clear markers for immunophenotyping of such a population. Most importantly, this PCPC could generate PC in an immune competent host, resulting in high levels of antibody production, fully recapitulating human MM disease. While this impressive study marks a significant improvement in our understanding of MM progenitor cells, several questions remain. First, what is the transcriptomics/epigenetics landscape of such PCPCs? Given that this study was done in a system with enhanced XBP-1 expression, do we expect to find such PCPC in XBP1 low expression cases? Can we identify a human equivalent population? How do we best translate such finding into therapeutic opportunities? Perhaps even clinical practice? We are hopeful that with the next-generation single cell “omics” technologies, these questions can be addressed in the foreseeable future and bring forward better care for patients with MM.
Kuehl WM, Bergsagel PL. Molecular pathogenesis of multiple myeloma and its premalignant precursor. J Clin Invest. 2012;122:3456-3463.
Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3:730-737.
Wu C, Alman BA. Side population cells in human cancers. Cancer Lett. 2008;268:1-9.
Matsui W, Wang Q, Barber JP, et al. Clonogenic multiple myeloma progenitors, stem cell properties, and drug resistance. Cancer Res. 2008;68:190-197.
Johnsen HE, Bøgsted M, Schmitz A, et al. The myeloma stem cell concept, revisited: from phenomenology to operational terms. Haematologica. 2016;101:1451-1459.
Conflict of Interests
Dr. Dong and Dr. Tahri indicated no relevant conflicts of interest. Dr. Ghobrial receives honoraria from Celgene, Bristol-Myers Squibb, Takeda, and Amgen; has a consulting or advisory role with Bristol-Myers Squibb, Novartis, Amgen, Takeda, Celgene, Cellectar, and Sanofi; receives travel, accommodations, and expenses from Bristol-Myers Squibb, Novartis, Celgene, Takeda, Janssen Oncology.
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