ALDH1 activity identifies tumor-initiating cells and links to chromosomal instability signatures in multiple myeloma

Zhou, Wen; Yang, Ye; Gu, Zhimin; Wang, He; Xia, Jiliang; Wu, Xiaosong; Zhan, Xin; Levasseur, Dana N.; Zhou, Yi; Janz, Siegfried; Tricot, Guido; Shi, Jumei; Zhan, Fenghuang

doi:10.1038/leu.2013.383

Cited by 59 publications

(60 citation statements)

References 14 publications

(17 reference statements)

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“…Indeed, successful engraftment of CD138 − subpopulation from MM patients, but not CD138 + , in NOD/SCID mice suggested that CD138 − myeloma cells were the principal myeloma initiating cells [19]. CD138 − myeloma cells express higher levels of aldehyde dehydrogenase [15, 20] and are resistant to anti-MM drugs, such as lenalidomide [15, 21]. …”

Section: Introductionmentioning

confidence: 99%

CD138-negative myeloma cells regulate mechanical properties of bone marrow stromal cells through SDF-1/CXCR4/AKT signaling pathway

Guo

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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As the second most prevalent hematologic malignancy, multiple myeloma (MM) remains incurable and relapses due to intrinsic or acquired drug resistance. Therefore, new therapeutic strategies that target molecular mechanisms responsible for drug resistance are attractive. Interactions of tumor cells with their surrounding microenvironment impact tumor initiation, progression and metastasis, as well as patient prognosis. This cross-talk is bidirectional. Tumor cells can also attract or activate tumor-associated stromal cells by releasing cytokines to facilitate their growth, invasion and metastasis. The effect of myeloma cells on bone marrow stromal cells (BMSCs) has not been well studied. In our study, we found that higher stiffness of BMSCs was not a unique characteristic of BMSCs from MM patients (M-BMSCs). BMSCs from MGUS (Monoclonal gammopathy of undetermined significance) patients were also stiffer than the BMSCs from healthy volunteers (N-BMSCs). The stiffness of M-BMSCs was enhanced when cocultured with myeloma cells. In contrast, no changes were seen in myeloma cell-primed MGUS- and N-BMSCs. Interestingly, our data indicated that CD138− myeloma cells, but not CD138+ cells, regulated M-BMSC stiffness. SDF-1 was highly expressed in the CD138− myeloma subpopulation compared with that in CD138+ cells. Inhibition of SDF-1 using AMD3100 or knocking-down CXCR4 in M-BMSCs blocked CD138− myeloma cells-induced increase in M-BMSC stiffness, suggesting a crucial role of SDF-1/CXCR4. AKT inhibition attenuated SDF-1-induced increases in M-BMSC stiffness. These findings demonstrate, for the first time, CD138− myeloma cell-directed cross-talk with BMSCs and reveal that CD138− myeloma cells regulate M-BMSC stiffness through SDF-1/CXCR4/AKT signaling.

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Section: Introductionmentioning

confidence: 99%

CD138-negative myeloma cells regulate mechanical properties of bone marrow stromal cells through SDF-1/CXCR4/AKT signaling pathway

Guo

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…BTK can now be added to the growing list of candidate myeloma stemness and drug resistance genes that have been uncovered by us (26,28,29,32,33) and others (34). The master stem cell factor NANOG – which is positively regulated by BTK according to this study and by RARα2 according to our previous report (26) – illustrates this point.…”

Section: Discussionmentioning

confidence: 99%

Bruton Tyrosine Kinase Is a Therapeutic Target in Stem-like Cells from Multiple Myeloma

Yang

Shi

et al. 2015

Cancer Research

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Ibrutinib (Imbruvica®), a small-drug inhibitor of Bruton tyrosine kinase (BTK), is currently undergoing clinical testing in patients with multiple myeloma (MM), yet important questions on the role of BTK in myeloma biology and treatment are outstanding. Using flow-sorted side population (SP) cells from human myeloma cell lines (HMCLs) and MM primary samples as surrogate fort the elusive multiple myeloma stem cell (MMSC), we found that elevated expression of BTK in myeloma cells leads to AKT/WNT/β-catenin-dependent up-regulation of key stemness genes (OCT4, SOX2, NANOG, MYC) and enhanced self-renewal. Enforced transgenic expression of BTK in myeloma cells increased features of cancer stemness, including clonogenicity and resistance to widely used myeloma drugs, whereas inducible knockdown of BTK abolished them. Furthermore, over-expression of BTK in myeloma cells promoted tumor growth in laboratory mice and rendered SP-derived tumors that contained high levels of BTK more sensitive to the selective, second-generation BTK inhibitor, CGI1746, than SP-derived tumors that harbored low levels of BTK. Taken together, these findings implicate BTK as a positive regulator of myeloma stemness and provide additional support for the clinical testing of BTK-targeted therapies in patients with myeloma.

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“…Our previous study demonstrated that ALDH1 + MM cells had much stronger capacities of proliferation and tumorigenicity, compared to ALDH1 − MM cells. Moreover, we found that ALDH1 + MM cells highly expressed chromosomal instability genes associated with drug resistance [55]. More recently, we demonstrate that member A1 of the ALDH1 family of proteins, ALDH1A1, was up-regulated in the course of myeloma therapy and progression, and that enforced expression of ALDH1A1 led to both increased tumorigenicity and resistance to two widely used myeloma drugs (doxorubicin, bortezomib) in vitro and in vivo [56].…”

Section: Drug Resistancementioning

confidence: 99%

Multiple myeloma cancer stem cells

et al. 2016

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Multiple myeloma (MM) remains incurable despite much progress that has been made in the treatment of the disease. MM cancer stem cell (MMSC), a rare subpopulation of MM cells with the capacity for self-renewal and drug resistance, is considered to lead to disease relapse. Several markers such as side population (SP) and ALDH1+ have been used to identify MMSCs. However, ideally and more precisely, the identification of the MMSCs should rely on MMSCs phenotype. Unfortunately the MMSC phenotype has not been properly defined yet. Drug resistance is the most important property of MMSCs and contributes to disease relapse, but the mechanisms of drug resistance have not been fully understood. The major signaling pathways involved in the regulation of self-renewal and differentiation of MMSCs include Hedgehog (Hh), Wingless (Wnt), Notch and PI3K/Akt/mTOR. However, the precise role of these signaling pathways needs to be clarified. It has been reported that the microRNA profile of MMSCs is remarkably different than that of non-MMSCs. Therefore, the search for targeting MMSCs has also been focused on microRNAs. Complex and mutual interactions between the MMSC and the surrounding bone marrow (BM) microenvironment sustain self-renewal and survival of MMSC. However, the required molecules for the interaction of the MMSC and the surrounding BM microenvironment need to be further identified. In this review, we summarize the current state of knowledge of MMSCs regarding their phenotype, mechanisms of drug resistance, signaling pathways that regulate MMSCs self-renewal and differentiation, abnormal microRNAs expression, and their interactions with the BM microenvironment.

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ALDH1 activity identifies tumor-initiating cells and links to chromosomal instability signatures in multiple myeloma

Cited by 59 publications

References 14 publications

CD138-negative myeloma cells regulate mechanical properties of bone marrow stromal cells through SDF-1/CXCR4/AKT signaling pathway

CD138-negative myeloma cells regulate mechanical properties of bone marrow stromal cells through SDF-1/CXCR4/AKT signaling pathway

Bruton Tyrosine Kinase Is a Therapeutic Target in Stem-like Cells from Multiple Myeloma

Multiple myeloma cancer stem cells

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