New insights into the normal and leukemic stem cell niche: a timely review.

Cytometry Part B (Clinical Cytometry) 84B:5–6 (2013) Editorial New Insights into the Normal and Leukemic Stem Cell Niche: A Timely Review The concept that tissue stem cells develop within spe- cialized microenvironments or niches originated from genetic studies of germ cell development in Drosophila (1), but much of what we know about stem cell niche biology has emerged from studies of the hematopoietic stem cell (HSC) niche, first conceptualized over 30 years ago by Schofield (2). In this issue of Clinical Cytometry, Krause et al. provide a comprehensive update on this rapidly moving field (3). Recent studies have demon- strated that the niche for normal HSC is complex, dynamic, and composed of multiple cellular components including osteoblasts, osteoclasts, mesenchymal stem cells, fibroblasts, adipocytes, macrophages, perivascular and endothelial cells, and sympathetic neurons and glial cells. Most of the new knowledge has emerged from so- phisticated in vivo imaging techniques such as two-pho- ton confocal microscopy (4), use of genetically modified mice that either lack critical niche signaling (5) or adhe- sion (6) molecules or express fluorescent reporter pro- teins in different niche lineages (7), and increasingly so- phisticated flow cytometric analysis and cell purification (8). Krause et al. summarize the current state of knowl- edge of the HSC niche, the relationship between the vas- cular and osteoblastic niches within the bone marrow microenvironment, and emerging efforts to manipulate the niche in clinical HSC transplantation. By contrast, the study of the influence of the bone marrow microenvironment on the pathogenesis of hema- topoietic malignancies is less well understood. Trans- plantation studies in mouse models of chronic (CML) and acute (AML) myeloid leukemias and xenotransplanta- tion of the corresponding human leukemias into immu- nodeficient mice have identified populations of malig- nant progenitors that are capable of initiating and sus- taining these leukemias (9). These so-called leukemia stem cells (LSC) are postulated to be the cause of relapse following induction of remission with chemo- therapy. By analogy to normal HSC, LSC are thought to reside in specific bone marrow niches that regulate their self-renewal, quiescence, and sensitivity to chemoradio- therapy. Until quite recently, we had little insight into the nature of these LSC niches (10) or whether they could represent a novel target for leukemia therapy. Early studies identified CD44 as an adhesion molecule binding selectins and hyaluronic acid that is expressed on both CML (11) and AML (12) stem cells, mediating homing, engraftment, and maintenance of LSC in trans- planted mice. Other studies showed a dependence of AML LSC on b1 integrins (13) and the chemokine q 2012 International Clinical Cytometry Society CXCL12 (14), contributing to chemotherapy resistance. Importantly, both anti-CD44 (Hoffmann-La Roche) and anti-CXCR4 (the receptor for CXLC12; Sanofi-Genzyme) therapies are currently in clinical trials for AML. Krause et al. discuss the rapid progress in this area, including exciting recent studies suggesting that the CML and AML stem cell niches are distinct and can be manipulated pharmacologically (15). What can we expect from this field in the future? A better understanding of the normal HSC niche should inform clinical strategies to improve HSC mobilization for both autologous and allogeneic transplantation, and to improve engraftment of recipients. Conversely, tar- geting the LSC niche has the promise to increase the response to cytotoxic and tyrosine kinase inhibitor ther- apy and eliminate residual leukemia, increasing the probability of cure. The review by Krause et al. illumi- nates both the progress made and the road ahead for translational and clinical investigators in this exciting arena. Richard A. Van Etten LITERATURE CITED 1. Papagiannouli F, Lohmann I. Shaping the niche: Lessons from the Drosophila testis and other model systems. Biotechnol J 2012;7: 2. Schofield R. The relationship between the spleen colony-forming cell and the haematopoietic stem cell. Blood Cells 1978;4:7–25. 3. Krause DS, Scadden DT, Preffer FI. The hematopoietic stem cell niche—Home for friend and foe? Cytometry B Clin Cytom 2013;84B:7–20. 4. Lo Celso C, Fleming HE, Wu JW, Zhao CX, Miake-Lye S, Fujisaki J, Cote D, Rowe DW, Lin CP, Scadden DT. Live-animal tracking of indi- vidual haematopoietic stem/progenitor cells in their niche. Nature 5. Fulzele K, Krause DS, Panaroni C, Saini V, Barry KJ, Liu X, Lotinun S, Baron R, Bonewald L, Feng JQ, et al. Myelopoiesis is regulated by osteocytes through Gsalpha-dependent signaling. Blood 2012,DOI: 10.1182/blood-2012-06-437160 (in press). 6. Goncharova V, Serobyan N, Iizuka S, Schraufstatter I, de Ridder A, Povaliy T, Wacker V, Itano N, Kimata K, Orlovskaja IA, et al. Hyalur- onan expressed by the hematopoietic microenvironment is required for bone marrow hematopoiesis. J Biol Chem 2012;287:25419– 7. Park D, Spencer JA, Koh BI, Kobayashi T, Fujisaki J, Clemens TL, Lin CP, Kronenberg HM, Scadden DT. Endogenous bone marrow MSCs are dynamic, fate-restricted participants in bone maintenance and regeneration. Cell Stem Cell 2012;10:259–272. *Correspondence to: Richard A. Van Etten, M.D., Ph.D., Molecular Oncology Research Institute and Division of Hematology/Oncology, Tufts Medical Center, 800 Washington Street, Box 5609, Boston, MA 02111. E-mail: Rvanetten@tuftsmedicalcenter.org Published online in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/cyto.b.21071