NG2 antigen is involved in leukemia invasiveness and central nervous system infiltration in MLL-rearranged infant B-ALL

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  • dc.contributor.author Prieto, Cristinaca
  • dc.contributor.author Iglesias Coma, Marca
  • dc.contributor.author Menéndez, Pabloca
  • dc.date.accessioned 2018-06-22T07:41:08Z
  • dc.date.available 2018-06-22T07:41:08Z
  • dc.date.issued 2018
  • dc.description.abstract Mixed-lineage leukemia (MLL)-rearranged (MLLr) infant B-cell acute lymphoblastic leukemia (iMLLr-B-ALL) has a dismal prognosis and is associated with a pro-B/mixed phenotype, therapy refractoriness and frequent central nervous system (CNS) disease/relapse. Neuron-glial antigen 2 (NG2) is specifically expressed in MLLr leukemias and is used in leukemia immunophenotyping because of its predictive value for MLLr acute leukemias. NG2 is involved in melanoma metastasis and brain development; however, its role in MLL-mediated leukemogenesis remains elusive. Here we evaluated whether NG2 distinguishes leukemia-initiating/propagating cells (L-ICs) and/or CNS-infiltrating cells (CNS-ICs) in iMLLr-B-ALL. Clinical data from the Interfant cohort of iMLLr-B-ALL demonstrated that high NG2 expression associates with lower event-free survival, higher number of circulating blasts and more frequent CNS disease/relapse. Serial xenotransplantation of primary MLL-AF4+ leukemias indicated that NG2 is a malleable marker that does not enrich for L-IC or CNS-IC in iMLLr-B-All. However, NG2 expression was highly upregulated in blasts infiltrating extramedullar hematopoietic sites and CNS, and specific blockage of NG2 resulted in almost complete loss of engraftment. Indeed, gene expression profiling of primary blasts and primografts revealed a migratory signature of NG2+ blasts. This study provides new insights on the biology of NG2 in iMLLr-B-ALL and suggests NG2 as a potential therapeutic target to reduce the risk of CNS disease/relapse and to provide safer CNS-directed therapies for iMLLr-B-ALL.
  • dc.description.sponsorship This work was supported by the European Research Council (CoG-2014-646903) and the Spanish Ministry of Economy-Competitiveness (SAF-SAF2013-43065) to PM, the Asociación Española Contra el Cáncer to CB and the ISCIII/FEDER (PI14/01191-PI13/00168) to CB and JCRM. PM acknowledges the financial support from the Obra Social La Caixa-Fundaciò Josep Carreras, the Inocente-Inocente Foundation and Generalitat de Catalunya. CP and DRM were funded by PFIS scholarships from the ISCIII. VA has financial support from L’Oreal-UNESCO. PM is investigator of the Spanish Cell Therapy cooperative network (TERCEL). We thank Antonio Agraz/Ignacio Varela (IBBTEC, Santander) for assisting in microarray analysis. We also thank Dr Patricia Pérez-Galán and Gael Roue (IDIBAPS, Barcelona, Spain) for helpful discussions on NG2 blocking experiments.
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Prieto C, López-Millán B, Roca-Ho H, Stam RW, Romero-Moya D, Rodríguez-Baena FJ. et al. NG2 antigen is involved in leukemia invasiveness and central nervous system infiltration in MLL-rearranged infant B-ALL. Leukemia. 2018 Mar;32(3):633-644. DOI: 10.1038/leu.2017.294
  • dc.identifier.doi http://dx.doi.org/10.1038/leu.2017.294
  • dc.identifier.issn 0887-6924
  • dc.identifier.uri http://hdl.handle.net/10230/34952
  • dc.language.iso eng
  • dc.publisher Nature Publishing Groupca
  • dc.relation.ispartof Leukemia. 2018 Mar;32(3):633-44
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/646903
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2013-43065
  • dc.rights Copyright © 2018 The Author(s). This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.other Leucèmia
  • dc.title NG2 antigen is involved in leukemia invasiveness and central nervous system infiltration in MLL-rearranged infant B-ALLca
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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