From www.bloodjournal.org by guest on February 9, 2018. For personal use only. BLOOD, 30 APRIL 2009 䡠 VOLUME 113, NUMBER 18
Much of the confusion could therefore be around methodology. It will be paramount to standardize the xenotransplantation approaches and to use optimized mouse models that offer the least hostile microenvironment for human cells.10 With these newer and more sensitive models, we may be surprised to find that many more populations have stem cell properties then previously thought. We look forward to continuing this debate. Olaf Heidenreich and Josef Vormoor Approval for these studies was obtained in Mu¨nster from the combined Ethics Committee of the Medical Faculty of Mu¨nster University and the regional chamber of physicians (Registration number 31 VVormoor) and in Newcastle upon Tyne from the Newcastle and North Tyneside Ethics Committee 2 (REC reference number 06/Q0906/79). Informed consent was obtained in accordance with the Declaration of Helsinki. Acknowledgments: This work was supported by grants from the Deutsche Jose´ Carreras Leuka¨mie-Stiftung eV (Mu¨nich, Germany), the North of England Childhood Cancer Research Fund (Newcastle upon Tyne, United Kingdom), and the JGW Patterson Foundation (Newcastle upon Tyne, United Kingdom). Conflict-of-interest disclosure: The authors declare no competing financial interests. Correspondence: Josef Vormoor, Northern Institute for Cancer Research, Newcastle University, Sir James Spence Institute, 4th Fl, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, United Kingdom; e-mail:
[email protected].
CORRESPONDENCE
4477
References 1. Cox CV, Diamanti P, Evely RS, Kearns PR, Blair A. Expression of CD133 on leukemia initiating cells in childhood ALL. Blood. 2009;113:3287-3291. 2. Cobaleda C, Gutierrez-Cianca N, Perez-Losada J, et al. A primitive hematopoietic cell is the target for the leukemic transformation in human philadelphiapositive acute lymphoblastic leukemia. Blood. 2000;95:1007-1013. 3. Cox CV, Evely RS, Oakhill A, Pamphilon DH, Goulden NJ, Blair A. Characterization of acute lymphoblastic leukemia progenitor cells. Blood. 2004;104: 2919-2925. 4. Castor A, Nilsson L, Astrand-Grundstrom I, et al. Distinct patterns of hematopoietic stem cell involvement in acute lymphoblastic leukemia. Nat Med. 2005; 11:630-637. 5. Hong D, Gupta R, Ancliff P, et al. Initiating and cancer-propagating cells in TELAML1-associated childhood leukemia. Science. 2008;319:336-339. 6. le Viseur C, Hotfilder M, Bomken S, et al. In childhood acute lymphoblastic leukemia, blasts at different stages of immunophenotypic maturation have stem cell properties. Cancer Cell. 2008;14:47-58. 7. Kong Y, Yoshida S, Saito Y, et al. CD34⫹CD38⫹CD19⫹ as well as CD34⫹CD38-CD19⫹ cells are leukemia-initiating cells with self-renewal capacity in human B-precursor ALL. Leukemia. 2008;22:1207-1213. 8. Morisot S, Wayne AS, Bohana-Kashtan O, et al. Leukemia stem cells (LSC) are frequent in childhood precursor B acute lymphoblastic leukemia (ALL) [abstract]. Blood. 2008;112:Abstract 1354. 9. Taussig DC, Miraki-Moud F, Anjos-Afonso F, et al. Anti-CD38 antibody-mediated clearance of human repopulating cells masks the heterogeneity of leukemia-initiating cells. Blood. 2008;112:568-575. 10. Dick JE. Looking ahead in cancer stem cell research. Nat Biotechnol. 2009;27: 44-46.
Response Stem cells in childhood acute lymphoblastic leukemia: identifying the most relevant targets for therapy We thank Heidenreich and Vormoor for their interest in our paper and we welcome the opportunity to respond. We agree with the authors that this is a very exciting time for research in acute lymphoblastic leukemia (ALL) stem cells and that standardization of methodologies will be paramount for generation of the most clinically relevant data. Indeed, in the discussion of our paper,1 we postulate that the apparent discrepancies in the published phenotypes of ALL stem cells could be attributed to several variables in the methodologies used. There are differences in the strains of immune-deficient mice used, the inoculation techniques, and in the age of the recipient animals. Kong et al used recipient mice at only 48 hours after birth.2 Interestingly, the abstract by Morisot et al, to which the authors refer, noted a similar frequency of leukemia stem cells using both nonobese diabetic severe combined immunedeficient (NOD/SCID) gamma (NSG) and the classic NOD/SCID strains, although the onset of leukemia was delayed in the NOD/SCIDs in some cases.3 It is also important to recognize that different subtypes of leukemia may also contribute to differences in the phenotype of the leukemia initiating cells. Two publications that reported multiple ALL cell phenotypes with leukemia engrafting capacity mainly used samples from high-risk cases.2,4 It is interesting to note in the paper by le Viseur4 and the table included in the letter that fewer CD19low cells were required to achieve engraftment levels similar to that observed with CD19high cells in the samples where these phenotypes were compared. Not only will it be crucial to develop xenotransplant models that are profoundly immune deficient to permit identification of any leukemia cells that have stem cell properties, it will also be
important to use more sophisticated assays that incorporate cell tracking or transplantation of finite cell numbers to discriminate between leukemia cells with extensive self-renewal ability and those that can proliferate to engraft animal models but have limited self-renewal capacity. Leukemia cells with greater self-renewal ability are likely to be the most relevant to target with novel therapeutic approaches. Paraskevi Diamanti and Allison Blair Acknowledgments: This work was supported by grants from Leukaemia Research, United Kingdom and the National Blood Authority, United Kingdom. Conflict-of-interest disclosure: The authors declare no competing financial interests. Correspondence: Dr Allison Blair, University of Bristol, Southmead Rd, Bristol BS10 5ND, United Kingdom; e-mail:
[email protected].
References 1.
Cox CV, Diamanti P, Evely RS, Kearns PR, Blair A. Expression of CD133 on leukemia initiating cells in childhood ALL. Blood. 2009;113:3287-3296.
2.
Kong Y, Yoshida S, Saito Y, et al. CD34⫹CD38⫹CD19⫹ as well as CD34⫹CD38-CD19⫹ cells are leukemia-initiating cells with self-renewal capacity in human B-precursor ALL. Leukemia. 2008;22:1207-1213.
3.
Morisot S, Wayne AS, Bohana-Kashtan O, et al. Leukemia stem cells (LSC) are frequent in childhood precursor B acute lymphoblastic leukemia (ALL) [abstract]. Blood. 2008;112:Abstract 1354.
4.
le Viseur C, Hotfilder M, Bomken S, et al. In childhood acute lymphoblastic leukemia, blasts at different stages of immunophenotypic maturation have stem cell properties. Cancer Cell. 2008;14:47-58.
From www.bloodjournal.org by guest on February 9, 2018. For personal use only.
2009 113: 4477 doi:10.1182/blood-2009-02-203786
Stem cells in childhood acute lymphoblastic leukemia: identifying the most relevant targets for therapy Paraskevi Diamanti and Allison Blair
Updated information and services can be found at: http://www.bloodjournal.org/content/113/18/4477.full.html Articles on similar topics can be found in the following Blood collections Information about reproducing this article in parts or in its entirety may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requests Information about ordering reprints may be found online at: http://www.bloodjournal.org/site/misc/rights.xhtml#reprints Information about subscriptions and ASH membership may be found online at: http://www.bloodjournal.org/site/subscriptions/index.xhtml
Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC 20036. Copyright 2011 by The American Society of Hematology; all rights reserved.
