Human acute myeloid leukemia CD34(+)/CD38(-) progenitor cells have decreased sensitivity to chemotherapy and fas-induced apoptosis, reduced immunogenicity, and impaired dendritic cell transformation capacities

The destruction of cells capable of initiating and maintaining leukemia cha llenges the treatment of human acute myeloid leukemia. Recently, CD34(+)/CD 38(-) leukemia progenitors have been defined as new leukemia-initiating cel ls less mature than colony-forming cells. Here we show that CD34(+)/CD38(-) leukemia precursors have reduced in vitro sensitivity to daunorubicin, a m ajor 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 a poptosis than CD34(+)/CD38(+) blasts. Moreover, the CD34(+)/CD38(-) leukemi c subpopulation induces a weaker mixed leukocyte reaction of responding T-l ymphocytes than the CD34(+)/CD38(+) leukemic counterpart, either in a MHC-u nmatched or MHC-matched settings. This weaker immunogenicity could be linke d to lower expression on CD34(+)/CD38(-) leukemia precursors of major immun e response molecules (MHC-DR, LFA-3, B7-1, or B7-2) than CD34(+)/CD38(+) le ukemic cells. Nonetheless, the susceptibility of the immature CD38(-) precu rsors to cytotoxicity was not different from the sensitivity of the CD38(+) counterpart. Finally, CD34(+)/CD38(-) leukemia precursors, in contrast wit h CD38(+) precursors, failed, under appropriate conditions, to differentiat e into dendritic cells, a central step for antigen recognition. This is to our knowledge the first demonstration that the very immature phenotype of C D34(+)/CD38(-) leukemic progenitors confers both chemotherapy resistance an d decreased capacities to induce an immune response. Because the susceptibi lity of the immature leukemia cells as cytotoxic targets is maintained, our data underline the importance of improving the initial steps of leukemia r ecognition, more particularly by defining optimal conditions of dendritic c ell transformation of the very immature hematopoietic precursors.