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 contr ast to normal stem cells although, both normal and leukemic CD34(+) cells d isplay comparable expression of c-kit or IL-15 receptor subunits, Interesti ngly, confocal microscopy analysis revealed that leukemic and most normal C D34(+) cells produce and secrete IL-15, as shown by its trafficking through the Golgi apparatus and early endosomes, However, only leukemic progenitor s express the membrane bound IL-15, Colocalization and internalization of I L-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 cons titutively pre-associated with the gamma c chain. Anti-IL-15 neutralizing m Ab treatment resulted in downregulation of gamma c chain and disruption of gamma c/Jak3 interaction in normal but had no effect in leukemic progenitor s. Our results suggest the existence in both normal and leukemic CD34(+) ce lls 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 cons titutive activation of gamma c are hallmarks of leukemic progenitors.