Abstract
Multiple myeloma (MM) remains a largely incurable, genetically heterogeneous plasma-cell malignancy that contains - just like many other cancers - a small fraction of clonogenic stem cell-like cells that exhibit pronounced self-renewal and differentiation capacities, but also pronounced drug resistance. These MM stem cells (MMSCs) are a controversial but highly significant issue in myeloma research because, in our opinion, they are at the root of the failure of anti-neoplastic chemotherapies to transform myeloma to a manageable chronic disease. Several markers including CD138-, ALDH1+ and SP have been used to identify MMSCs; however, no single marker is reliable for the isolation of MMSC. Nonetheless, it is now known that MMSCs depend on self-renewal and pro-survival pathways, such as AKT, Wnt/β-catenin, Notch and Hedgehog, which can be targeted with novel drugs that have shown promise in pre-clinical and clinical trials. Here, we review the pathways of myeloma "stemness", the interactions with the bone marrow microenvironment that promote drug resistance, and the obstacles that must be overcome to eradicate MMSCs and make myeloma a curable disease.
Highlights
MM, the second most common blood cancer (13%), is a genetically complex, clonal plasma-cell malignancy that accounts for 1% of all newly diagnosed neoplasms [1,2,3]
Myelomagenesis is a multistep process that begins as asymptomatic monoclonal gammopathy of undetermined significance (MGUS), evolves to smoldering MM (SMM), continues to progress to symptomatic disease as defined by clinical and laboratory criteria, and end organ damage [9], and eventually leads to an aggressive, refractory neoplasia, comparable to blast crisis in CML or Richter’s syndrome in chronic lymphocytic leukemia (CLL)
Our studies showed that expression of ALDH1A1, the predominant isoform of ALDH1 in myeloma cells, leads to up-regulation of 9-cis retinoic acid (9CRA) [52]
Summary
MM, the second most common blood cancer (13%), is a genetically complex, clonal plasma-cell malignancy that accounts for 1% of all newly diagnosed neoplasms [1,2,3]. (3) BTK, which is not expressed in normal plasma cells, is often aberrantly expressed in myeloma including MMSCs. Activation of BTK by targeted phosphorylation in the plasma membrane leads to cross-signaling with the WNT/b-catenin (4) and AKT (5) pathways.
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