Altered natural killer cell differentiation in CD34+ progenitors from chronic myeloid leukemia patients

IL-15 and SCF fail to induce NK differentiation and proliferation of CD34(+) hematopoietic progenitors from chronic myeloid leukemia patients in contrast to normal stem cells although, both normal and leukemic CD34(+) cells display comparable expression of c-kit or IL-15 receptor subunits, Interestingly, confocal microscopy analysis revealed that leukemic and most normal CD34(+) cells produce and secrete IL-15, as shown by its trafficking through the Golgi apparatus and early endosomes, However, only leukemic progenitors express the membrane bound IL-15, Colocalization and internalization of IL-15R beta/gamma c and IL-15R alpha/gamma c complexes indicated that IL-15 was specifically uptaken by leukemic progenitors. We also demonstrated that in both normal and leukemic progenitors, the signaling kinase Jak3 is constitutively pre-associated with the gamma c chain. Anti-IL-15 neutralizing mAb treatment resulted in downregulation of gamma c chain and disruption of gamma c/Jak3 interaction in normal but had no effect in leukemic progenitors. Our results suggest the existence in both normal and leukemic CD34(+) cells of a constitutive production of a bioactive IL-15 that does not lead to NK differentiation and further indicate that membrane bound IL-15 and constitutive activation of gamma c are hallmarks of leukemic progenitors.