Caractérisation génétique et épigénétique d'une translocation chromosomique mettant en jeu l'hétérochromatine constitutive 1Q12 dans les hémopathies malignes

L'hétérochromatine constitutive du chromosome 1 (bande 1q12) est fréquemment réarrangée dans les hémopathies malignes et les tumeurs solides. Ces réarrangements pourraient jouer un rôle important lors de la tumorigénèse. Ils pourraient être l'équivalent moléculaire des remaniements observés chez la drosophile et la levure, ayant comme conséquence la répression de l'expression génique par un mécanisme type effet de position. La caractérisation génétique et épigénétique d'une translocation der(2)t(1;2)(q12;p13), impliquant l'hétérochromatine constitutive 1q12 dans une lignée de lymphome B malins montre une hétérochromatinisation en cis des séquences en 2p conséquente de la translocation avec l'hétérochromatine 1q12. Ce travail met en évidence l'existence d'un effet de position provoqué par un réarrangement avec l'hétérochromatine constitutive 1q12 dans un modèle de cellules B malignes.GRENOBLE1-BU Sciences (384212103) / SudocSudocFranceF

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