CD49d is overexpressed by trisomy 12 chronic lymphocytic leukemia cells: evidence for a methylation-dependent regulation mechanism.
CD49d is a negative prognosticator in chronic lymphocytic leukemia (CLL), expressed by ~40% of CLL cases and associated with aggressive, accelerated clinical courses. In this study, analyzing CD49d expression in a wide CLL cohort (n = 1200) belonging to different cytogenetic groups, we report that trisomy 12 CLL almost universally expressed CD49d and were characterized by the highest CD49d expression levels among all CD49d(+) CLL. Through bisulfite genomic sequencing, we demonstrated that, although CD49d(+)/trisomy 12 CLL almost completely lacked methylation of the CD49d gene, CD49d(-)/no trisomy 12 CLL were overall methylated, the methylation levels correlating inversely to CD49d expression (P = .0001). Consistently, CD49d expression was recovered in CD49d(-) hypermethylated CLL cells upon in vitro treatment with the hypomethylating agent 5-aza-2'-deoxycytidine. This may help explain the clinicobiological features of trisomy 12 CLL, including the high rates of cell proliferation and disease progression, lymph node involvement, and predisposition to Richter syndrome transformation.
Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico, I.R.C.C.S., Aviano (PN), Italy;
Antonella
A
Zucchetto
Chiara
C
Caldana
Dania
D
Benedetti
Erika
E
Tissino
Francesca Maria
FM
Rossi
Evelyn
E
Hutterer
Federico
F
Pozzo
Riccardo
R
Bomben
Michele
M
Dal Bo
Giovanni
G
D'Arena
Francesco
F
Zaja
Gabriele
G
Pozzato
Francesco
F
Di Raimondo
Tanja N
TN
Hartmann
Davide
D
Rossi
Gianluca
G
Gaidano
Giovanni
G
Del Poeta
Valter
V
Gattei
D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D002478:Cells, Cultured; D002881:Chromosomes, Human, Pair 12; D000077209:Decitabine; D018450:Disease Progression; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D039441:Integrin alpha4 / Q000235:genetics* / Q000378:metabolism; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D008745:Methylation; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D016019:Survival Analysis; D014314:Trisomy / Q000473:pathology*
D039441:Integrin alpha4; D000077209:Decitabine; D001374:Azacitidine