Promiscuous MYC locus rearrangements hijack enhancers but mostly super-enhancers to dysregulate MYC expression in multiple myeloma.
Promiscuous MYC locus rearrangements hijack enhancers but mostly super-enhancers to dysregulate MYC expression in multiple myeloma.
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多发性骨髓瘤(MM)的MYC基因重排--通常是移位、插入、缺失和倒位的复杂组合--被认为是一种晚期进展事件，通常不涉及免疫球蛋白基因。然而，据报道，生发中心激活MYC表达会导致MGUS倾向的小鼠品系进展为MM。虽然以前在16%的MM中检测到MYC重排，但我们发现近50%的MM中存在MYC重排，包括阴燃MM，在某些情况下它们是异质性的。重排将MYC重新定位在与常规增强子相关的有限数量的基因附近，但主要与超级增强子相关(例如，IgH、IGL、IGK、NSMCE2、TXNDC5、FAM46C、FOX03、IGJ、PRDM1)。MYC重排与MYC单等位基因表达显著增加有关，但缺乏重排的MM肿瘤的双等位MYC表达水平显著高于MGUS。我们还表明，MYC的生发中心激活不会在很少发生自发性MGUS的小鼠品系中导致多发性骨髓瘤。在MGUS/MM的转变中，MYC表达的增加通常是双等位基因，但如果有MYC重排，有时也可能是单等位基因。我们的数据表明，MYC重排，无论它们何时发生在MM发病过程中，都提供了一个有助于肿瘤自主性的事件。
MYC locus rearrangements – often complex combinations of translocations, insertions, deletions, and inversions - in multiple myeloma (MM) were thought to be a late progression event, which often did not involve immunoglobulin genes. Yet germinal center activation of MYC expression has been reported to cause progression to MM in an MGUS prone mouse strain. Although previously detected in 16% of MM, we find MYC rearrangements in nearly 50% of MM, including smoldering MM, and they are heterogeneous in some cases. Rearrangements reposition MYC near a limited number of genes associated with conventional enhancers, but mostly with super-enhancers (e.g., IGH, IGL, IGK, NSMCE2, TXNDC5, FAM46C, FOXO3, IGJ, PRDM1). MYC rearrangements are associated with a significant increase of MYC expression that is monoallelic, but MM tumors lacking a rearrangement have bi-allelic MYC expression at significantly higher levels than in MGUS. We also show that germinal center activation of MYC does not cause MM in a mouse strain that rarely develops spontaneous MGUS. It appears that increased MYC expression at the MGUS/MM transition usually is bi-allelic, but sometimes can be mono-allelic if there is a MYC rearrangement. Our data suggests that MYC rearrangements, regardless of when they occur during MM pathogenesis, provide one event that contributes to tumor autonomy.
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影响因子：
64.8
作者：
Ernst, Jason;Kheradpour, Pouya;Mikkelsen, Tarjei S.;Shoresh, Noam;Ward, Lucas D.;Epstein, Charles B.;Zhang, Xiaolan;Wang, Li;Issner, Robbyn;Coyne, Michael;Ku, Manching;Durham, Timothy;Kellis, Manolis;Bernstein, Bradley E.
通讯作者：
Bernstein, Bradley E.
DOI：
10.1073/pnas.93.24.13931
发表时间：
1996-11-26
影响因子：
11.1
作者：
Bergsagel, PL;Chesi, M;Kuehl, WM
通讯作者：
Kuehl, WM
影响因子：
11.4
作者：
Chng, W-J;Huang, G. F.;Chung, T. H.;Ng, S. B.;Gonzalez-Paz, N.;Troska-Price, T.;Mulligan, G.;Chesi, M.;Bergsagel, P. L.;Fonseca, R.
通讯作者：
Fonseca, R.
影响因子：
11.4
作者：
Bertrand, P.;Bastard, C.;Tilly, H.
通讯作者：
Tilly, H.
影响因子：
64.5
作者：
Hnisz D;Abraham BJ;Lee TI;Lau A;Saint-André V;Sigova AA;Hoke HA;Young RA
通讯作者：
Young RA