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-15Rbeta/gammac and IL-15Ralpha/gammac 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 gammac chain. Anti-IL-15 neutralizing mAb treatment resulted in down-regulation of gammac chain and disruption of gammac/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 gammac are hallmarks of leukemic progenitors. Oncogene (2000).
Carayol
G
G
INSERM U487, Institut Gustave Roussy, 39, rue Camille Desmoulins, 94805 Villejuif, France.
Giron-Michel
J
J
Azzarone
B
B
Castagna
L
L
Cambier
N
N
Mishal
Z
Z
Bourhis
J H
JH
Chouaib
S
S
Caignard
A
A
D018952:Antigens, CD34 / Q000378:metabolism*; D002454:Cell Differentiation; D002455:Cell Division; D002460:Cell Line; D006801:Humans; D019409:Interleukin-15 / Q000378:metabolism / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000473:pathology* / Q000502:physiology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016131:Lymphocyte Subsets / Q000473:pathology* / Q000502:physiology; D018613:Microscopy, Confocal; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D019089:Stem Cell Factor / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D018952:Antigens, CD34; C508024:IL15RA protein, human; D019409:Interleukin-15; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2; D019089:Stem Cell Factor