CD34⁺/CD38⁻ acute myelogenous leukemia cells aberrantly express CD82 which regulates adhesion and survival of leukemia stem cells.
To identify molecular targets in leukemia stem cells (LSCs), this study compared the protein expression profile of freshly isolated CD34(+) /CD38(-)  cells with that of CD34(+) /CD38(+)  counterparts from individuals with acute myelogenous leukemia (n = 2, AML) using isobaric tags for relative and absolute quantitation (iTRAQ). A total of 98 proteins were overexpressed, while six proteins were underexpressed in CD34(+) /CD38(-)  AML cells compared with their CD34(+) /CD38(+)  counterparts. Proteins overexpressed in CD34(+) /CD38(-)  AML cells included a number of proteins involved in DNA repair, cell cycle arrest, gland differentiation, antiapoptosis, adhesion, and drug resistance. Aberrant expression of CD82, a family of adhesion molecules, in CD34(+) /CD38(-)  AML cells was noted in additional clinical samples (n = 12) by flow cytometry. Importantly, down-regulation of CD82 in CD34(+) /CD38(-)  AML cells by a short hairpin RNA (shRNA) inhibited adhesion to fibronectin via up-regulation of matrix metalloproteinases 9 (MMP9) and colony forming ability of these cells as assessed by transwell assay, real-time RT-PCR, and colony forming assay, respectively. Moreover, we found that down-regulation of CD82 in CD34(+) /CD38(-)  AML cells by an shRNA significantly impaired engraftment of these cells in severely immunocompromised mice. Taken together, aberrant expression of CD82 might play a role in adhesion of LSCs to bone marrow microenvironment and survival of LSCs. CD82 could be an attractive molecular target to eradicate LSCs.
Department of Immunology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan.
Chie
C
Nishioka
Takayuki
T
Ikezoe
Mutsuo
M
Furihata
Jing
J
Yang
Satoshi
S
Serada
Tetsuji
T
Naka
Atsuya
A
Nobumoto
Sayo
S
Kataoka
Masayuki
M
Tsuda
Keiko
K
Udaka
Akihito
A
Yokoyama
D051997:ADP-ribosyl Cyclase 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018952:Antigens, CD34 / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000502:physiology; D006801:Humans; D007124:Immunoenzyme Techniques; D051861:Kangai-1 Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D010446:Peptide Fragments / Q000032:analysis; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D014407:Tumor Cells, Cultured
D018952:Antigens, CD34; C497688:CD82 protein, human; D018398:Homeodomain Proteins; D051861:Kangai-1 Protein; D010446:Peptide Fragments; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C064658:RAG-1 protein; D051997:ADP-ribosyl Cyclase 1; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9