attenuated P. yoelii sporozoites, and that mice were tolerant to PyCSP after two doses of the vaccine but that the third dose somehow overcame the tolerance to PyCSP-mediated protection. This is unlikely, but as no T-cell assays were reported, confirmation or refu-tation of this explanation awaits additional experiments.

Kumar and colleagues have significantly advanced our understanding of protective immunity in malaria. However, their results demonstrate the difficulty of determining the relative importance of a single protein in the protective immunity elicited by a vac-cine consisting of a live, attenuated, whole, infectious agent. The results also underscore the incompleteness of our understanding of immunodominance and subdominance14. Nonetheless, these PyCSP-tolerant mice are a unique resource that will allow scientists to clarify the role of PyCSP in protective immu-nity, and perhaps further the development of a highly effective vaccine that will reduce the misery wreaked by malaria. ■

Stephen L. Hoffman is at Sanaria Inc., 12115 Parklawn Drive, Suite L, Rockville, Maryland 20852, USA.e-mail: slhoffman@sanaria.com

1. Breman, J. G., Egan, A. & Keusch, G. T. Am. J. Trop. Med. Hyg. 64 (Suppl. 1–2), iv–vii (2001).

2. Clyde, D. F., Most, H., McCarthy, V. C. & Vanderberg, J. P. Am. J. Med. Sci. 266, 169–177 (1973).

3. Rieckmann, K. H., Carson, P. E., Beaudoin, R. L., Cassells, J. S. & Sell, K. W. Trans. R. Soc. Trop. Med. Hyg. 68, 258–259 (1974).

4. Hoffman, S. L. et al. J. Infect. Dis. 185, 1155–1164 (2002).5. Luke, T. C. & Hoffman, S. L. J. Exp. Biol. 206, 3803–3808

(2003).6. Gardner, M. J. et al. Nature 419, 498–511 (2002).7. Hoffman, S. L., Subramanian, G. M., Collins, F. H. & Venter,

J. C. Nature 415, 702–709 (2002).8. Kumar, K. A. et al. Nature 444, 937–940 (2006).9. Ballou, W. R. et al. Lancet 1 (8545), 1277–1281 (1987). 10. Herrington, D. A. et al. Nature 328, 257–259 (1987). 11. Dame, J. B. et al. Science 225, 593–599 (1984).12. Kester, K. E. et al. J. Infect. Dis. 183, 640–647 (2001).13. Hoffman, S. L., Rogers, W. O., Carucci, D. J. & Venter, J. C.

Nature Med. 4, 1351–1353 (1998).14. Holtappels, R. B. I. F. Futura 20, 157–163 (2005).

Potential competing financial interests: declared; details accompany the article on Nature’s website.

LEUKAEMIA

Niche retreats for stem cellsDavid A. Williams and Jose A. Cancelas

Leukaemic cells and normal blood-producing cells relate differently to their surroundings. This concept has now been extended to leukaemic stem cells, suggesting a fresh approach to therapy.

Maintaining good neighbourhood relations is important for all cells in multicellular organ-isms. The complex interactions between adjacent cells and with their local microen-vironment support the growth, development and function of the cells — and cancer cells are no exception. Writing in Nature Medicine, Jin et al.1 and Krause et al.2 report convincing evi-dence from two different models that CD44, a cell-surface receptor that mediates cell–cell contacts, helps the cells that give rise to leu-kaemia to engraft in the bone marrow. Nota-bly, the normal cells that give rise to blood in the bone marrow do not apparently rely to the same extent on this receptor for their function, suggesting that CD44 might be a therapeutic target for leukaemia.

Blood cells develop from immature cells known as haematopoietic stem cells and pro-genitor cells (HSC/Ps). In addition to being programmed with the capability to make blood cells, these HSC/Ps also divide to maintain their own numbers, a process termed self-renewal. HSC/Ps have a defined spatial organization in the bone-marrow cavity, with the most-primi-tive cells being located in stem-cell niches3 near the endosteum of the bone — the layer of con-nective tissue that lines the cavity. But HSC/Ps don’t exist in isolation; they prefer company.

For instance, they thrive in culture only when they are in contact with stromal cells derived from the bone marrow4. In the body, the endo-steal niche may also include osteoblast cells, which are responsible for bone formation, and it seems that these cells too may have a direct role in HSC/P function5,6, but the molecular pathways involved still need to be completely defined.

At least some HSC/Ps may also reside in a vascular niche located in the vascular network of the bone marrow (the sinusoids)7,8. In each of these stem-cell niches, cell-surface recep-tors expressed on HSC/Ps, including CD44, c-kit, CXCR4 and β1 integrins, seem to be vital for the localization and retention in the bone marrow.

The HSC/Ps that are circulating in the blood and engraft into the marrow may gain entry into the bone-marrow cavity in a man-ner somewhat analogous to the better-under-stood process by which white blood cells exit blood vessels to travel to sites of inflammation. This involves first rolling and becoming firmly attached to the vessel wall, and then travers-ing this endothelial boundary and migrating into the complex cellular milieu of the bone-marrow cavity. Ultimately, these cells settle into a haematopoietic microenvironment or

stem-cell niche (Fig. 1, overleaf). Interrupting this migration process prevents engraftment or retention of normal HSC/Ps in the bone marrow, stopping these cells from self-renew-ing and contributing to blood formation. It is not yet known whether circulating HSC/Ps play any physiological role in normal haemato-poiesis, or whether they are merely travelling from one spot in the bone marrow to take up residence in another.

So how does this ordered scheme go awry in leukaemia? The current view of how this can-cer arises posits that there are leukaemia stem cells (LSCs) that share characteristics with HSC/Ps, but that initiate and maintain leu-kaemia instead of normal blood-cell develop-ment9. However, the nature of LSC interaction with the supporting bone-marrow microenvi-ronment, where leukaemia presumably arises, is unclear.

Both Jin et al.1 and Krause et al.2 based their work on the idea that — similar to normal HSC/Ps — LSCs depend upon interactions within a specific niche, the LSC niche. Nota-bly, the investigators hypothesized that some of these interactions are specific for LSCs alone and therefore could be a target for therapy. In both reports, different forms of CD44 seem to be crucial components in the interaction of LSCs with a supportive haematopoietic microenvironment. Both papers show that altering the function of CD44 leads to delay in the progression of leukaemia in mouse models of the disease.

CD44 is a multifunctional, ubiquitously expressed protein that helps cells to adhere to other cells and to matrix proteins, and it par-ticipates in the recruitment of certain white blood cells to sites of inflammation and in their migration through lymphatic tissues. In HSC/Ps, the isoforms of CD44 bind to its ligand, hyaluronic acid, which is expressed in the bone-marrow sinusoids and in the endo-steal region. This binding seems to be specifi-cally important for allowing LSCs to settle in the bone marrow and for subsequent leukae-mia development (Fig. 1)1,2.

Jin et al.1 used samples from patients suf-fering from acute myeloid leukaemia to seed tumours in mice that lack an immune system, so that the animals would not reject the human cells. The authors report that treatment with an activating antibody directed against CD44 — which would be expected to block any inter-actions of CD44 with other proteins — signifi-cantly reduced tumour burden and prolonged survival of the leukaemia-engrafted mice.

Mechanistic studies suggest that dual molec-ular pathways are involved in the effect of CD44 inhibition on leukaemia progression. Antibody treatment of the putative LSCs from the human patients differentially inhibited the migration of these cells to the bone marrow and spleen. Antibody treatment also directly altered the fate of LSCs by inducing development into a more mature state. The relevance of this lat-ter finding in vivo was suggested by the direct

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Corticalbone

Bloodstream

Bonemarrow

CD44 ligands

CD44

RollingFirm

adhesion

Endosteal niche

Vascular niche

β1 integrins

LeukaemichaematopoiesisNormal

haematopoiesis

Leukaemic stem cell

Leukaemic progenitor

Mature leukaemic cell

Normal stem cell

Normal progenitor

Migrating leukaemic cell

injection of antibody-treated human cells into the mouse marrow cavity. Such injected cells failed to establish a robust leukaemia even though these cells were not required to traverse the usual engraftment pathways.

Krause et al.2 used a mouse model of chronic myelogenous leukaemia, which is caused by the expression of the Bcr–Abl fusion protein. They report similar — but not identical — results. To examine the role of CD44, the authors expressed Bcr–Abl in mouse HSC/Ps that were genetically deficient in CD44, and transplanted these cells into recipient mice of the same strain as the donors (to avoid rejection). In these studies, the progression of Bcr–Abl-induced, leukaemia-like disease was delayed in recipi-ent mice. In addition, similar to the results of Jin et al.1, antibody treatment of recipients of Bcr–Abl-expressing LSCs also slowed disease progression. However, unlike the studies with human leukaemia cells, the direct injection of antibody-treated LSCs led to disease similar to that in control-treated cells.

The basis for this difference in the two stud-ies is not clear, but it could be related to the specific tumour type (acute versus chronic), model (cross-species versus same-strain trans-plant) or antibody used. This difference may be quite important because it suggests that at least one mechanism noted above — the direct effect of CD44 binding to its ligand on LSC dif-ferentiation — is potentially not occurring in both models. Additional studies are clearly needed.

The different effect of antibody treatment on LSCs and normal HSC/Ps is intriguing

Figure 1 | Putative migration of stem cells between the bloodstream and bone marrow. Normal stem cells require multiple receptors to adhere firmly to the endothelium (the cell layer that lines blood vessels). They then make their way to putative endosteal and vascular stem-cell niches in the bone marrow. The β1 integrins are shown as an example of the adhesion molecules involved in migration and adhesion of normal stem cells to their niches. Jin et al.1 and Krause et al.2 show that leukaemia stem cells instead seem to depend on the expression of CD44 to localize to the bone marrow and initiate a leukaemia-like disease in mouse models.

and important, but the basis for the differ-ence is not yet clearly defined. Work by Jin et al.1 suggests this difference may be because different isoforms of CD44 are expressed by LSCs compared with HSC/Ps. Krause et al.2

suggest instead that the differential effect may relate to the relative level of CD44 expression in the leukaemia-initiating cells. Similar issues have plagued past studies implicating CD44 in the homing and engraftment of normal HSC/Ps into the bone marrow. In either case, the results are not yet definitive. In spite of this continued uncertainty, these reports1,2 provide significant insight into the biol-ogy of leukaemia-initiating cells with stem-cell-like characteristics and normal HSC/Ps with respect to interaction with the haemato-poietic micro environment. Such differences in the behaviour of the normal and leukae-mic cells could well provide new avenues for targeted therapies. ■

David A. Williams is in the Division of Experimental Hematology, Cincinnati Children’s Research Foundation, Cincinnati, Ohio 45229, USA. Jose A. Cancelas is in the Hoxworth Blood Center, University of Cincinnati Medical Center, Cincinnati, Ohio 45267, USA.e-mail: David.Williams@cchmc.org

1. Jin, L., Hope, K. J., Zhai, Q., Smadja-Joffe, F. & Dick, J. E. Nature Med. 12, 1167–1174 (2006).

2. Krause, D. S., Lazarides, K., von Andrian, U. H. & Van Etten, R. A. Nature Med. 12, 1175–1180 (2006).

3. Lord, B. I., Testa, A. G. & Hendry, J. H. Blood 46, 65–72 (1975).

4. Dexter, T. M. et al. J. Cell Physiol. 91, 335–344 (1976).5. Nilsson, S. K., Johnston, H. M. & Coverdale, J. A. Blood 97,

2293–2299 (2001).6. Calvi, L. M. et al. Nature 425, 841–846 (2003).7. Kiel, M. J., Yilmaz, O. H., Iwashita, T., Terhorst, C. &

Morrison, S. J. Cell 121, 1109–1121 (2005).8. Cancelas, J. A. et al. Nature Med. 11, 886–891

(2005).9. Lapidot, T. et al. Nature 367, 645–648 (1994).

SEMICONDUCTOR ELECTRONICS

Organic crystals at largePaul Heremans

Fabricating large-scale semiconducting surfaces for the flexible screens of the future is a bothersome business. A simple technique for growing single-crystal organic semiconductors brings new vision to the field.

On page 913 of this issue, Zhenan Bao and col-leagues (Briseno et al.)1 describe a method for nucleating and growing single-crystal organic semiconductors over electrodes on an arbi-trary substrate, and so producing extended arrays of high-performance electronic transis-tors. Their method represents a step towards practical applications of high-quality, but fragile, single crystals of organic semiconduc-tors, and could show the way to high-perform-ance electronic devices that extend over large and flexible surfaces.

Transistors are minuscule switches that lie at the heart of all electronic devices — com-puters, memory sticks, displays, you name it. At the heart of every transistor is a channel of semiconductor material that bridges two

electrodes. An electrical potential applied at a third electrode, the ‘gate’, controls whether current is allowed over this bridge or not. The most successful semiconductor for such switching applications, omnipresent in today’s electronics, is silicon.

Silicon transistors can be processed on two very different types of substrate. The first is a thin, single-crystal, nearly defect-free silicon substrate called a wafer. Wafers are limited in size, but can be processed in sophisticated ways to bear a mind-boggling density of nanoscale transistors: a wafer 300 millimetres in diam-eter can hold hundreds or thousands of chips, each one containing up to a billion transistors. Wafer-based technologies are continuously scaling to larger transistor counts and density

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