This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Costello, R. T. Articles by Olive, D. Search for Related Content PubMed PubMed Citation Articles by Costello, R. T. Articles by Olive, D.

Human Acute Myeloid Leukemia CD34⁺/CD38^- Progenitor Cells Have Decreased Sensitivity to Chemotherapy and Fas-induced Apoptosis, Reduced Immunogenicity, and Impaired Dendritic Cell Transformation Capacities¹

Unité d’Immunologie des Tumeurs [R. T. C., F. M., B. B., H. C., D. O.], Département d’Hématologie [R. T. C., D. S., C. A., J-A. G.], Institut Paoli-Calmettes, Université de la Méditerranée, and Unité INSERM U119 [D. O.], 13009 Marseille, France

The destruction of cells capable of initiating and maintaining leukemia challenges the treatment of human acute myeloid leukemia. Recently, CD34⁺/CD38^- leukemia progenitors have been defined as new leukemia-initiating cells less mature than colony-forming cells. Here we show that CD34⁺/CD38^- leukemia precursors have reduced in vitro sensitivity to daunorubicin, a major drug used in leukemia treatment, in comparison with the CD34⁺/CD38⁺ counterpart, and increased expression of multidrug resistance genes (mrp/lrp). These precursors show lower expression of Fas/Fas-L and Fas-induced apoptosis than CD34⁺/CD38⁺ blasts. Moreover, the CD34⁺/CD38^- leukemic subpopulation induces a weaker mixed leukocyte reaction of responding T-lymphocytes than the CD34⁺/CD38⁺ leukemic counterpart, either in a MHC-unmatched or MHC-matched settings. This weaker immunogenicity could be linked to lower expression on CD34⁺/CD38^- leukemia precursors of major immune response molecules (MHC-DR, LFA-3, B7-1, or B7-2) than CD34⁺/CD38⁺ leukemic cells. Nonetheless, the susceptibility of the immature CD38^- precursors to cytotoxicity was not different from the sensitivity of the CD38⁺ counterpart. Finally, CD34⁺/CD38^- leukemia precursors, in contrast with CD38⁺ precursors, failed, under appropriate conditions, to differentiate into dendritic cells, a central step for antigen recognition. This is to our knowledge the first demonstration that the very immature phenotype of CD34⁺/CD38^- leukemic progenitors confers both chemotherapy resistance and decreased capacities to induce an immune response. Because the susceptibility of the immature leukemia cells as cytotoxic targets is maintained, our data underline the importance of improving the initial steps of leukemia recognition, more particularly by defining optimal conditions of dendritic cell transformation of the very immature hematopoietic precursors.

This article has been cited by other articles:

				D. C. Hassane, M. L. Guzman, C. Corbett, X. Li, R. Abboud, F. Young, J. L. Liesveld, M. Carroll, and C. T. Jordan Discovery of agents that eradicate leukemia stem cells using an in silico screen of public gene expression data Blood, June 15, 2008; 111(12): 5654 - 5662. [Abstract] [Full Text] [PDF]

				Q. Sun, C. T. Kong, F. P. Huang, and L. C. Chan Aberrant dendritic cell differentiation initiated by the Mll-Een fusion gene does not require leukemic transformation J. Leukoc. Biol., January 1, 2008; 83(1): 173 - 180. [Abstract] [Full Text] [PDF]

				U. Ganapati, H. T. Tan, M. Lynch, M. Dolezal, S. de Vos, and J. C. Gasson Modeling Notch Signaling in Normal and Neoplastic Hematopoiesis: Global Gene Expression Profiling in Response to Activated Notch Expression Stem Cells, August 1, 2007; 25(8): 1872 - 1880. [Abstract] [Full Text] [PDF]

				C. Li, D. G. Heidt, P. Dalerba, C. F. Burant, L. Zhang, V. Adsay, M. Wicha, M. F. Clarke, and D. M. Simeone Identification of Pancreatic Cancer Stem Cells Cancer Res., February 1, 2007; 67(3): 1030 - 1037. [Abstract] [Full Text] [PDF]

				A. van Rhenen, N. Feller, A. Kelder, A. H. Westra, E. Rombouts, S. Zweegman, M. A. van der Pol, Q. Waisfisz, G. J. Ossenkoppele, and G. J. Schuurhuis High Stem Cell Frequency in Acute Myeloid Leukemia at Diagnosis Predicts High Minimal Residual Disease and Poor Survival Clin. Cancer Res., September 15, 2005; 11(18): 6520 - 6527. [Abstract] [Full Text] [PDF]

				F. Behbod and J. M. Rosen Will cancer stem cells provide new therapeutic targets? Carcinogenesis, April 1, 2005; 26(4): 703 - 711. [Abstract] [Full Text] [PDF]

				A. Cignetti, A. Vallario, I. Roato, P. Circosta, B. Allione, L. Casorzo, P. Ghia, and F. Caligaris-Cappio Leukemia-Derived Immature Dendritic Cells Differentiate into Functionally Competent Mature Dendritic Cells That Efficiently Stimulate T Cell Responses J. Immunol., August 15, 2004; 173(4): 2855 - 2865. [Abstract] [Full Text] [PDF]

				D. G. Gilliland, C. T. Jordan, and C. A. Felix The Molecular Basis of Leukemia Hematology, January 1, 2004; 2004(1): 80 - 97. [Abstract] [Full Text] [PDF]

				H. Kim, K. A. Whartenby, R. W. Georgantas III, J. Wingard, and C. I. Civin Human CD34+ Hematopoietic Stem/Progenitor Cells Express High Levels of FLIP and Are Resistant to Fas-Mediated Apoptosis Stem Cells, March 1, 2002; 20(2): 174 - 182. [Abstract] [Full Text] [PDF]