Trisomy 12 chronic lymphocytic leukemia cells exhibit upregulation of integrin signaling that is modulated by NOTCH1 mutations.
The leukocyte adhesion cascade is important in chronic lymphocytic leukemia (CLL), as it controls migration of malignant cells into the pro-survival lymph node microenvironment. Circulating trisomy 12 CLL cells have increased expression of the integrins CD11a and CD49d, as well as CD38, but the tissue expression of these and other molecules, and the functional and clinical sequelae of these changes have not been described. Here, we demonstrate that circulating trisomy 12 CLL cells also have increased expression of the integrins CD11b, CD18, CD29, and ITGB7, and the adhesion molecule CD323. Notably, there was reduced expression of CD11a, CD11b, and CD18 in trisomy 12 cases with NOTCH1 mutations compared with wild type. Trisomy 12 cells also exhibit upregulation of intracellular integrin signaling molecules CALDAG-GEFI, RAP1B, and Ras-related protein ligand, resulting in enhanced very late antigen-4 [VLA-4] directed adhesion and motility. CD38 expression in CLL has prognostic significance, but the increased CD38 expression in trisomy 12 CLL cells must be taken into account in this subgroup, and the threshold of CD38 positivity should be raised to 40% for this marker to retain its prognostic value. In conclusion, trisomy 12 CLL cells exhibit functional upregulation of integrin signaling, with β2-integrin expression being modulated by NOTCH1 mutation status.
Department of Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom;
John C
JC
Riches
Department of Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom;
Conor J
CJ
O'Donovan
Department of Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom;
Sarah J
SJ
Kingdon
Department of Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom;
Fabienne
F
McClanahan
Department of Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom;
Andrew J
AJ
Clear
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA;
Donna S
DS
Neuberg
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA;
Lillian
L
Werner
Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Wexner Medical Center, Columbus, OH; and.
Carlo M
CM
Croce
Department of Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom;
Alan G
AG
Ramsay
Moores Cancer Center, University of California, San Diego, La Jolla, CA.
Laura Z
LZ
Rassenti
Moores Cancer Center, University of California, San Diego, La Jolla, CA.
Thomas J
TJ
Kipps
Department of Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom;
John G
JG
Gribben
D000368:Aged; D002465:Cell Movement / Q000235:genetics; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics / Q000378:metabolism; D015973:Gene Expression Regulation, Leukemic; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000096:biosynthesis* / Q000235:genetics; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009360:Neoplastic Cells, Circulating / Q000378:metabolism* / Q000473:pathology; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014314:Trisomy / Q000235:genetics / Q000473:pathology; D015854:Up-Regulation; D020668:rap GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism
D020662:Guanine Nucleotide Exchange Factors; D016023:Integrins; C497761:NOTCH1 protein, human; D009363:Neoplasm Proteins; C415483:RASGRP2 protein, human; D051881:Receptor, Notch1; C116753:RAP1B protein, human; D020668:rap GTP-Binding Proteins