Dormant tumor cells develop cross-resistance to apoptosis induced by CTLs or imatinib mesylate via methylation of suppressor of cytokine signaling 1.
In the BCR/ABL DA1-3b mouse model of acute myelogenous leukemia, dormant tumor cells may persist in the host in a state of equilibrium with the CD8(+) CTL-mediated immune response by actively inhibiting T cells. Dormant tumor cells also show a progressive decrease of suppressor of cytokine signaling 1 (SOCS1) gene expression and a deregulation of the Janus-activated kinase/signal transducers and activators of transcription (JAK/STAT) pathway due to methylation of the SOCS1 gene. Dormant tumor cells were more resistant to apoptosis induced by specific CTLs, but resistance decreased when SOCS1 expression was restored via demethylation or gene transfer. AG490 JAK2 inhibitor decreased the resistance of dormant tumor cells to CTLs, but MG132 proteasome inhibitor was effective only in SOCS1-transfected cells. Thus, SOCS1 regulation of the JAK/STAT pathways contributes to the resistance of tumor cells to CTL-mediated killing. Resistance of dormant tumor cells to apoptosis was also observed when induced by irradiation, cytarabine, or imatinib mesylate, but was reduced by SOCS1 gene transfer. This cross-resistance to apoptosis was induced by interleukin 3 (IL-3) overproduction by dormant tumor cells and was reversed with an anti-IL-3 antibody. Thus, tumor cells that remain dormant for long periods in the host in spite of a specific CTL immune response may deregulate their JAK/STAT pathways and develop cross-resistance to various treatments through an IL-3 autocrine loop. These data suggest possible new therapeutic targets to eradicate dormant tumor cells.
Saudemont
Aurore
A
INSERM, U837, Institut de Recherche sur le Cancer de Lille, Université Lille, Lille, France.
Hamrouni
Abdelbasset
A
Marchetti
Philippe
P
Liu
Jizhong
J
Jouy
Nathalie
N
Hetuin
Dominique
D
Colucci
Francesco
F
Quesnel
Bruno
B
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology*; D001549:Benzamides; D019175:DNA Methylation; D015973:Gene Expression Regulation, Leukemic; D020868:Gene Silencing; D000068877:Imatinib Mesylate; D053612:Janus Kinases / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008809:Mice, Inbred C3H; D010879:Piperazines / Q000276:immunology / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D011743:Pyrimidines / Q000276:immunology / Q000494:pharmacology*; D050791:STAT Transcription Factors / Q000378:metabolism; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics* / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D014162:Transfection
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D050791:STAT Transcription Factors; C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D000068877:Imatinib Mesylate; D053612:Janus Kinases