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

Leukemia volume 28, pages 1155–1158 (2014)Cite this article

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Increased aldehyde dehydrogenase (ALDH) activity has been found in murine and human hematopoietic stem cells and human multiple myeloma stem cells (MMSCs).1, 2, 3 ALDHs are a group of NAD(P)-dependent enzymes involved in drug resistance and retinoic acid metabolism, which are crucial for the protection of stem cells against toxic endogenous and exogenous aldehydes. Recently, the isolation and functional analysis of ALDH1-positive (ALDH1+) cells have been greatly facilitated by the development of the Aldefluor assay.4 Matsui et al.3 reported that ALDH1 activity is increased in MMSCs.5 In the present study, we have addressed the question of whether ALDH1+ MM cells can initiate MM tumor formation and have evaluated the functional role of ALDH1 in MM cell growth, clonogenic ability and cell signaling.

To determine whether ALDH1+ cells have increased clonogenic potential, the ALDH1+ fraction was selected from the ARP1 and KMS12BM cell lines. A total of 10 000 ALDH1+ and ALDH1– cells per well were seeded in triplicates in a 12-well plate on methylcellulose.6 After 2 weeks at 37 °C, the number of colonies from ALDH1+ and ALDH1– cells was compared. The colony-forming capacity of ALDH1+ cells in both ARP1 and KMS12BM cells showed greater colony formation capacity than ALDH– cells (5.68% vs 1.15% in APR1 and 2.97% vs 0.83% in KMS12BM, Figure 1d). Tumorigenicity of ALDH1+ MM cells was evaluated using an in vivo mouse model. A total of ∼10 000 ALDH1+ and 10 000 ALDH1– cells from ARP1 and KMS12BM cells were injected into the NOD.Cg-Rag1 mice (n=5 for each group), respectively. After 8 weeks, ARP1-ALDH1+ and KMS12BM-ALDH1+ cells showed significantly greater capacity of tumor formation compared with their ALDH1– cells correspondingly (Figures 1e and f).

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Acknowledgements

We thank Drs Apollina Goel and Jeanine Schibler for providing expert assistance. This work was supported by the National Cancer Institute grants R01CA115399 (to GT), R01CA152105 (to FZ), R01CA151354 (to SJ) and R21CA143887 (to FZ), the MMRF Senior (to FZ, 2008 and 2010), the leukemia lymphoma society TRP (to FZ, 2010 and 2011), institutional start-up funds from the Department of Internal Medicine, Carver School of Medicine, University of Iowa (to FZ and GT), and the National Natural Science Foundation of China, P. R. China (No. 81228016 to FZ and JS).

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  1. W Zhou and Y Yang: These authors contributed equally to this work and are co-first authors.

  2. J Shi and F Zhan: These authors share senior authorship.

Authors and Affiliations

  1. Department of Internal Medicine, University of Iowa, Carver College of Medicine, Iowa City, IA, USA

    W Zhou, Y Yang, Z Gu, H Wang, J Xia, D Levasseur, Y Zhou, G Tricot & F Zhan

  2. Department of Hematology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China

    X Wu & J Shi

  3. Vanderbilt University, Nashville, TN, USA

    X Zhan

  4. Department of Pathology, University of Iowa, Carver College of Medicine, Iowa City, IA, USA

    S Janz

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Zhou, W., Yang, Y., Gu, Z. et al. ALDH1 activity identifies tumor-initiating cells and links to chromosomal instability signatures in multiple myeloma. Leukemia 28, 1155–1158 (2014). https://doi.org/10.1038/leu.2013.383

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