Origin of the Myeloma Stem Cell

Abstract SCI-4

Increasing evidence suggest that most human cancers consist of phenotypically and functionally heterogeneous cell types. Moreover, in some tumors, phenotypic-functional relationships exist and the capacity for clonogenic growth and self-renewal may be restricted to specific cell types. In multiple myeloma, malignant plasma cells make up the vast majority of tumor cells, phenotypically characterize the disease, and are responsible for clinical symptoms. However, myeloma plasma cells also appear terminally differentiated similar to their normal counterparts and incapable of long-term proliferation. Similar to other laboratories, we have identified minor populations of B cells that share the identical immunoglobulin gene rearrangements as the malignant plasma cells in most myeloma patients. We have further studied the functional capacity of these clonotypic B cells and found that they have ability to produce ectopic tumor growth both in vitro and in immunodeficient mice that can recapitulate human disease.^1,2 Moreover, these cells are relatively resistant to several agents currently used to treat multiple myeloma suggesting that they have the capacity to persist following treatment and are responsible for tumor regrowth and disease relapse. In order to inhibit these drug resistant cancer stem cells, we have studied cellular pathways that regulate the self-renewal of normal adult stem cells and found that several, including the developmental pathway Hedgehog, are potential therapeutic targets.³ Finally, as these concepts are translated to the clinic, several challenges have emerged including the ability to detect activity against myeloma stem cells that make up only a minority of the overall tumor burden.⁴ To this end, we have begun to develop biomarker strategies to serially quantify myeloma stem cells in patients undergoing treatment and will examine their utility as clinical endpoints.

1. Matsui W, Huff CA, Wang Q, et al. Characterization of clonogenic multiple myeloma cells. Blood. 2004;103:2332–2336.

2. Matsui W, Wang Q, Barber JP, et al. Clonogenic Multiple Myeloma Progenitors, Stem Cell Properties, and Drug Resistance. Cancer Research. 2008;68:190–197.

3. Peacock CD, Wang Q, Gesell GS, et al. Hedgehog signaling maintains a tumor stem cell compartment in multiple myeloma. Proceedings of the National Academy of Sciences, USA. 2007;104:4048–4053.

4. Huff CA, Matsui W, Smith BD, Jones RJ. The paradox of response and survival in cancer therapeutics. Blood. 2006;107:431–434.