BCR/ABL oncogene directly controls MHC class I chain-related molecule A expression in chronic myelogenous leukemia.
MHC class I chain-related molecules (MIC) participate in immune surveillance of cancer through engagement of the NKG2D-activating receptor on NK and T cells. Decreased NKG2D expression and function upon chronic exposure to NKG2D ligands and/or soluble forms of MIC (sMIC) may participate in immune escape. In chronic myeloid leukemia, a malignancy caused by the BCR/ABL fusion oncoprotein, we showed cell surface expression of MICA on leukemic, but not healthy, donor hemopoietic CD34+ cells. At diagnosis, chronic myeloid leukemia patients had abnormally high serum levels of sMICA and weak NKG2D expression on NK and CD8+ T cells, which were restored by imatinib mesylate (IM) therapy. In the BCR/ABL+ cell line K562, IM decreased both surface MICA/B expression and NKG2D-mediated lysis by NK cells. Silencing BCR/ABL gene expression directly evidenced its role in the control of MICA expression. IM did not affect MICA mRNA levels, but decreased MICA protein production and release. Sucrose density gradient fractionation of K562 cytoplasmic extracts treated with IM showed a shift in the distribution of MICA mRNA from the polysomal toward the monosomal fractions, consistent with decreased translation. Among the major pathways activated by BCR/ABL that regulate translation, PI3K and mammalian target of rapamycin were shown to control MICA expression. These data provide evidence for direct control of MICA expression by an oncogene in human malignancy and indicate that posttranscriptional mechanisms may participate in the regulation of MICA expression.
Institut National de la Santé et de la Recherche Médicale, Unité 622, Centre d'Investigations Biomédicales, Laboratoire d'Immunologie et d'Histocompatibilité, Hôpital Saint-Louis, Paris, France. nicolas.boissel@sls.ap-hop-paris.fr
Nicolas
N
Boissel
Delphine
D
Rea
Vannary
V
Tieng
Nicolas
N
Dulphy
Manuel
M
Brun
Jean-Michel
JM
Cayuela
Philippe
P
Rousselot
Ryad
R
Tamouza
Philippe
P
Le Bouteiller
François-Xavier
FX
Mahon
Alexander
A
Steinle
Dominique
D
Charron
Hervé
H
Dombret
Antoine
A
Toubert
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018952:Antigens, CD34 / Q000378:metabolism; D001549:Benzamides; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016313:Genes, abl; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use; D011494:Protein Kinases / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic / Q000378:metabolism; D055607:Receptors, Natural Killer Cell; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology; D058570:TOR Serine-Threonine Kinases
D018952:Antigens, CD34; D001549:Benzamides; D015395:Histocompatibility Antigens Class I; D000068877:Imatinib Mesylate; D055655:NK Cell Lectin-Like Receptor Subfamily K; D019869:Phosphatidylinositol 3-Kinases; D010879:Piperazines; D011494:Protein Kinases; D011743:Pyrimidines; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011971:Receptors, Immunologic; D055607:Receptors, Natural Killer Cell; D058570:TOR Serine-Threonine Kinases; C527085:KLRK1 protein, human; C099187:MHC class I-related chain A; C546842:MTOR protein, human