Differences in nuclear positioning of 1q12 pericentric heterochromatin in normal and tumor B lymphocytes with 1q rearrangements.
The frequent rearrangement of chromosome band 1q12 constitutive heterochromatin in hematologic malignancies suggests that this rearrangement plays an important pathogenetic role in these diseases. The oncogenic mechanisms linked to 1q12 heterochromatin are unknown. Constitutive heterochromatin can epigenetically regulate gene function through the formation of transcriptional-silencing compartments. Thus, as a first step toward understanding whether 1q12 rearrangements might compromise such activity in tumor cells, we investigated the 3-D organization of the 1q12 heterochromatin domain (1q12HcD) in normal and tumor B lymphocytes. Strikingly, in normal B cells, we showed that the 1q12HcD dynamically organizes to the nuclear periphery in response to B-cell receptor engagement. Specifically, we observed an almost twofold increase in 1q12Hc domains at the extreme nuclear periphery in activated versus resting B lymphocytes. Remarkably, 1q12Hc organization was noticeably altered in tumor cells that showed structural alterations of 1q12; the 1q12Hc domains were significantly displaced from the extreme nuclear periphery compared to normal activated B lymphocytes (P > 0.0001), although overall peripheral localization was maintained. In a case in which there was a translocation of IGL enhancer to 1q, the altered nuclear positioning of the 1q12HcD was even more pronounced (5% of the 1q12Hc domains at the nuclear periphery compared to 20% in other lymphoma lines), and we were able to mimic this effect in two additional B-cell tumor lines by treatment with trichostatin A, a histone deacetylase (HDAC) inhibitor. Taken together, these results point to the 1q12HcD having a specific, nonrandom, and regulated peripheral organization in B lymphocytes. This organization is significantly disrupted in lymphoma cells harboring 1q rearrangements.
Barki-Celli
Leila
L
Lymphoma Research Group, INSERM E353, Institut Albert Bonniot-Faculté de Médecine, Université Joseph Fourier Grenoble 1, Domaine de la Merci, La Tronche Cedex, France.
Lefebvre
Christine
C
Le Baccon
Patricia
P
Nadeau
Gwenael
G
Bonnefoix
Thierry
T
Usson
Yves
Y
Vourc'h
Claire
C
Khochbin
Saadi
S
Leroux
Dominique
D
Callanan
Mary
M
D001402:B-Lymphocytes / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D002051:Burkitt Lymphoma / Q000235:genetics* / Q000648:ultrastructure; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D002869:Chromosome Aberrations; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D006570:Heterochromatin / Q000235:genetics* / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D017404:In Situ Hybridization, Fluorescence; D008213:Lymphocyte Activation; D008224:Lymphoma, Follicular / Q000235:genetics* / Q000648:ultrastructure; D014178:Translocation, Genetic
D006570:Heterochromatin; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C012589:trichostatin A