AML engraftment in the NOD/SCID assay reflects the outcome of AML: implications for our understanding of the heterogeneity of AML

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The nonobese diabetic/severe combined immunodeficient (NOD/SCID) assay is the current model for assessment of human normal and leukemic stem cells. We explored why 51% of 59 acute myeloid leukemia (AML) patients were unable to initiate leukemia in
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  doi:10.1182/blood-2005-06-2325Prepublished online October 18, 2005; Preudhomme, Bryan D Young, Ama Z Rohatiner, T A Lister and Dominique BonnetDaniel J Pearce, David Taussig, Kazem Zibara, Lan-Lan Smith, Christopher M Ridler, Claude  implications for our understanding of the heterogeneity of AMLAML engraftment in the NOD/SCID assay reflects the outcome of AML:  (4217 articles)Neoplasia  (3716 articles)Clinical Trials and Observations  Articles on similar topics can be found in the following Blood collections  http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#repub_requests Information about reproducing this article in parts or in its entirety may be found online at:  http://bloodjournal.hematologylibrary.org/site/misc/rights.xhtml#reprints Information about ordering reprints may be found online at:  http://bloodjournal.hematologylibrary.org/site/subscriptions/index.xhtml Information about subscriptions and ASH membership may be found online at: digital object identifier (DOIs) and date of initial publication. theindexed by PubMed from initial publication. Citations to Advance online articles must include final publication). Advance online articles are citable and establish publication priority; they areappeared in the paper journal (edited, typeset versions may be posted when available prior to Advance online articles have been peer reviewed and accepted for publication but have not yet  Copyright 2011 by The American Society of Hematology; all rights reserved.20036.the American Society of Hematology, 2021 L St, NW, Suite 900, Washington DC Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by  For personal use only.by guest on June 3, 2013. bloodjournal.hematologylibrary.orgFrom   AML engraftment in the NOD/SCID assay reflects the outcome of AML: implications for our understanding of the heterogeneity of AML. Short Title: AML NOD/SCID engraftment and prognosis risk group Daniel J. Pearce 1* , David Taussig 1/2* , Kazem Zibara 1/3 ,   Lan-Lan Smith 1/3 , Christopher M. Ridler 1 , Claude Preudhomme 4 , Bryan D. Young 3 , Ama Z Rohatiner 2 , T Andrew Lister 2  and Dominique Bonnet 1 *DP and DT contributed equally to this work This work was supported by Cancer Research UK and a National Institute of Health Grant No. HL-64856-03 to D. Bonnet. Corresponding Author: Dr Dominique Bonnet Hematopoietic Stem Cell Laboratory Cancer Research UK London Research Institute 44 Lincoln’s Inn Fields London WC2A 3PX Tel: 020 72693281 Fax: 020 72693581 d.bonnet@cancer.org.uk    Heading: Hematopoiesis Text word count: 4560 excluding references Abstract word count: 182 2 Cancer Research UK Medical Oncology Unit, St. Bartholomew’s Hospital, West Smithfield, London, EC1A 7BE.   1 Hematopoietic Stem Cell Laboratory London Research Institute Cancer Research UK London WC2A 3PX   3 Medical Oncology Laboratory, Cancer Research UK, Queen Mary & St Bartholomew’s Medical School, Charterhouse Square, London EC1M 6BQ 4 Laboratoire d'hématologie A, Hopital Calmette Bd du professeur Leclercq 59037 Lille, France  Blood First Edition Paper, prepublished online October 18, 2005; DOI 10.1182/blood-2005-06-2325   Copyright © 2005 American Society of Hematology  For personal use only.by guest on June 3, 2013. bloodjournal.hematologylibrary.orgFrom    2 Abstract   The non-obese diabetic/severe combined immunodeficient (NOD/SCID) assay is the current model for assessment of human normal and leukemic stem cells. We explored why 51% of 59 acute myeloid leukemia (AML) patients were unable to initiate leukemia in NOD/SCID mice. Increasing the cell dose, using more permissive recipients and alternative tissue sources, did not cause AML engraftment in most previously non-engrafting AML samples. Homing of AML cells to the marrow was the same between engrafters and non-engrafters. FLT-3 ITD and nucleophosmin mutations occurred at a similar frequency in engrafters and non-engrafters. The only variable that was related to engraftment ability was the karyotypically-defined risk stratification of individual AML cases. Interestingly, follow-up of younger patients with intermediate-risk AML revealed a significant difference in overall survival between NOD/SCID-engrafting and non-engrafting AMLs. Hence, the ability of AML to engraft in the NOD/SCID assay seems to be an inherent property of AML cells, independent of homing, conditioning or cell frequency/source, which is directly related to prognosis. Our results suggest an important difference between leukemic initiating cells between engrafting and non-engrafting AML cases that correlates with treatment response. For personal use only.by guest on June 3, 2013. bloodjournal.hematologylibrary.orgFrom    3 Introduction The non-obese diabetic/severe combined immunodeficient (NOD/SCID) xenotransplantation assay is currently the model of choice for assessment of transplantable human hematopoietic stem cells (HSC). This approach has been crucial to our understanding of human hematopoiesis; providing reliable determination of the phenotypes of repopulating cells 1 , and elucidating previously undescribed HSC populations. 2  More recently, a novel mouse strain has been developed by backcrossing β 2 microglobulin-null (B2m-/-) mice onto the NOD/SCID background. The resulting B2-/-NOD/SCID strain, in addition to the B-cell, T-cell, complement and partial NK defects that define the NOD/SCID model, has a complete lack of NK cell activity. 3  Hence, this model is reportedly even more permissive to xenotransplantation than the srcinal NOD/SCID strain. 4  Acute myeloid leukemia (AML) is characterized by a relentless accumulation of immature, abnormal hematopoietic cells in the bone marrow and peripheral blood. It has been postulated that AML is a disease maintained by leukemic stem cells and may be organized in a similar way to normal hematopoiesis. Indeed, only a subset of AML cells are capable of forming colonies in vitro  and a smaller fraction can maintain colony production for six weeks whilst on feeder layers 5 . Definitive proof that a small population of leukemic stem cells produce the AML blasts, comes from six-week primary and secondary engraftment experiments in NOD/SCID mice 6 . Further studies have revealed that these SCID-Leukemia initiating cells (SL-IC) share many properties with normal HSC, namely phenotype, quiescence, and in vitro  CXCR-4 mediated migration. 6-8  AML is an extremely heterogeneous disease and since there are so many different known genetic abnormalities (and probably many more unknown), AML may be thought of as a collection of different diseases that have the same myeloid morphology. Indeed, for patients less than 60 years of age the single most important prognostic factor is the karyotype. 9,10  AML cases are currently divided via karyotype into the treatment groups of poor, intermediate and favorable prognosis. The majority of patients have an intermediate risk karyotype and the outcome of these patients is variable as well as difficult to predict using prospective tests. Previous studies have reported that approximately 70% of AML cases will engraft in the NOD/SCID assay. 11  Although many groups have utilized the For personal use only.by guest on June 3, 2013. bloodjournal.hematologylibrary.orgFrom    4NOD/SCID assay, the majority have only assessed the AML cases capable of engraftment. 12-15  Few studies have addressed the variables that affect engraftment itself. 16  Various factors affecting normal hematopoietic cell engraftment have been identified and may be applicable to AML NOD/SCID engraftment. A complex series of interactions of adhesion molecules, cytokines, chemokines and their receptors is responsible for the homing of transplanted human hematopoietic cells from the peripheral injection site to the bone marrow. 17  A major role in hematopoietic cell homing is attributed to the interaction between the chemokine SDF-1 and its receptor CXCR-4. 18  Overexpression of CXCR-4 on human CD34 +  cells results in an increased ability to home to and engraft NOD/SCID marrows. 19  Furthermore, antibody blocking studies have revealed that engraftment of human hematopoietic cells in NOD/SCID mice is dependent on the interaction between CXCR-4 and SDF-1. 20  In AML, although both in vitro  transendothelial migration and the level of in vivo  NOD/SCID bone marrow homing are dependent on CXCR-4, it is not clear whether the actual ability to engraft NOD/SCID mice is dependent on the CXCR-4/SDF-1 axis. 8,21  Here, we examined 59 AML patients for their ability to initiate leukemia in NOD/SCID mice. We established via morphology, phenotype, genotype and RNA expression that when AML engrafted, the AML produced was very similar to the patients’ disease. We then investigated variables known to affect normal cell engraftment for their ability to cause AML engraftment. Increasing the cell dose, more intensive conditioning, more permissive recipients and alternative tissue sources (bone marrow), did not cause AML engraftment in previously non-engrafting AML samples. Both the CXCR-4 expression and in vivo  homing of AML cells were the same between engrafters and non-engrafters. FLT-3 ITD and nucleophosmin mutations occurred at a similar frequency in engrafters and non-engrafters. The only variable, which did seem to be related to engraftment ability, was the karyotype of individual AML cases. Interestingly, follow-up of younger (< 60 years) intermediate-risk AML cases revealed a statistically significant difference in overall survival between NOD/SCID-engrafting and non-engrafting cases of AML. Hence, the NOD/SCID assay appears to reproduce an AML very similar to the patients’ disease and the ability to engraft seems to be an inherent property of AML cells, that is independent of homing, conditioning or cell dose/source, but is directly related to prognosis. For personal use only.by guest on June 3, 2013. bloodjournal.hematologylibrary.orgFrom 
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