Altered natural killer cell differentiation in CD34+ progenitors from Chronic Myeloid Leukemia patients

Abstract

IL-15 and SCF fail to induce NK di erentiation 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 tra cking through the Golgi apparatus and early endosomes. However, only leukemic progenitors express the membrane bound IL-15. Colocalization and internalization of IL-15Rb/gc and IL-15Ra/gc complexes indicated that IL-15 was speci®cally uptaken by leukemic progenitors. We also demonstrated that in both normal and leukemic progenitors, the signaling kinase Jak3 is constitutively pre-associated with the gc chain. Anti-IL-15 neutralizing mAb treatment resulted in downregulation of gc chain and disruption of gc/Jak3 interaction in normal but had no e ect 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 di erentiation and further indicate that membrane bound IL-15 and constitutive activation of gc are hallmarks of leukemic progenitors.

Endogenous IL-15 Sustains Recruitment of IL-2Rβ and Common γ and IL-2-Mediated Chemokine Production in Normal and Inflamed Human Gingival Fibroblasts

“…3, C and D). This observation suggests that translation or intracellular trafficking of IL-15 in HGF is regulated, which is in agreement with recent reports showing that IL-15 is constitutively expressed on fibroblasts from human spleen and skin and also on human monocytes and leukemic progenitors without any IL-15 secretion (22)(23)(24)(25)(26). Considering these findings, it is conceivable that HGF express endogenous IL-15 as the membranebound IL-15, which is the transcript encoding 48 aa-IL-15.…”

“…Another neutralizing anti-IL-15 mAb showed the same results and cross-linking of IL-15/IL-2R␤/␥ c or IL-2R␤/␥ c by addition of mAbs to the molecules followed by antimouse IgG did not alter the expression of IL-2R␤ and ␥ c (data not shown), indicating that neutralizing anti-IL-15 mAb inhibited binding of IL-15 to IL-2R␤ and ␥ c on the cell surface, and excludes the possibility that the anti-IL-15 induced inhibitory effect by cross-linking of IL-15/IL-2R␤/␥ c . Recent reports showed that neutralizing the anti-IL-15 mAb inhibited ␥ c expression in CD34 ϩ hemopoietic progenitors (26,30), but had no clear effect on IL-2R␤. Another report showed that the formation of the IL-15/IL-15R␣ complex on lymphoid cell surfaces induced a trans-endosomal recycling of IL-15 leading to the persistence of surface-bound IL-15 (31).…”

“…The 48 aa-IL-15 is targeted to the secretory pathway with low secretion potential (19,20), whereas the 21 aa-IL-15 appears to be restricted to the cytoplasm and nucleus (19,21). Recent reports showed that IL-15 is constitutively expressed on fibroblasts from human spleen and skin and also on human monocytes and leukemic progenitors without any IL-15 secretion (22)(23)(24)(25)(26). However, it is still unclear which of the isoforms are expressed on the cell surface.…”

Fibroblasts from Human Spleen Regulate NK Cell Differentiation from Blood CD34+ Progenitors Via Cell Surface IL-15

“…In contrast, blood-derived cells, including monocytes, monoblastoid cells, and leukemic progenitors, have been reported to constitutively express membrane-associated IL-15 without any IL-15 secretion (27)(28)(29). This membrane form has been proposed to be the bioactive form of IL-15 (27) and the result of IL-15 mobilization from intracellular stores to the membrane (30).…”

Defects of immune surveillance offer new insights into the pathophysiology and therapy of myelodysplastic syndromes

“…18 The possibility to differentiate NK cells in vitro has raised the question of NK-cell differentiation in patients with myeloid disorders. We showed that the in vitro development of NK cells from CML progenitors was altered, 19 suggesting that such alterations may lead to the decreased function of peripheral NK cells described in CML patients. We also found a severe alteration in NK-cell differentiation from CD34 þ cells derived from MDS patients.…”