Deregulation of Aiolos expression in chronic lymphocytic leukemia is associated with epigenetic modifications.
Chronic lymphocytic leukemia (CLL) is characterized by a clonal accumulation of mature neoplastic B cells that are resistant to apoptosis. Aiolos, a member of the Ikaros family of zinc-finger transcription factors, plays an important role in the control of mature B lymphocyte differentiation and maturation. In this study, we showed that Aiolos expression is up-regulated in B-CLL cells. This overexpression does not implicate isoform imbalance or disturb Aiolos subcellular localization. The chromatin status at the Aiolos promoter in CLL is defined by the demethylation of DNA and an enrichment of euchromatin associated histone markers, such as the dimethylation of the lysine 4 on histone H3. These epigenetic modifications should allow its upstream effectors, such as nuclear factor-κB, constitutively activated in CLL, to gain access to promoter, resulting up-regulation of Aiolos. To determine the consequences of Aiolos deregulation in CLL, we analyzed the effects of Aiolos overexpression or down-regulation on apoptosis. Aiolos is involved in cell survival by regulating the expression of some Bcl-2 family members. Our results strongly suggest that Aiolos deregulation by epigenetic modifications may be a hallmark of CLL.
Hôpital Pitié-Salpêtrière, Université Pierre et Marie Curie (UPMC) Paris VI, Inserm, Paris, France.
Katy
K
Billot
Jérémie
J
Soeur
Fanny
F
Chereau
Issam
I
Arrouss
Hélène
H
Merle-Béral
Meng-Er
ME
Huang
Dominique
D
Mazier
Véronique
V
Baud
Angelita
A
Rebollo
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D018899:CpG Islands; D019175:DNA Methylation; D017931:DNA Primers / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D006801:Humans; D051740:Ikaros Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D066298:In Vitro Techniques; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D013347:Subcellular Fractions / Q000378:metabolism
D002843:Chromatin; D017931:DNA Primers; C497239:IKZF1 protein, human; C106285:IKZF3 protein, human; D016328:NF-kappa B; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D051740:Ikaros Transcription Factor