Centre for Lymphoid Cancer, BC Cancer, Vancouver, BC, Canada.
Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, BC, Canada.
Blood. 2024 Aug 1;144(5):525-540. doi: 10.1182/blood.2024024251.
Rearrangements that place the oncogenes MYC, BCL2, or BCL6 adjacent to superenhancers are common in mature B-cell lymphomas. Lymphomas with diffuse large B-cell lymphoma (DLBCL) or high-grade morphology with both MYC and BCL2 rearrangements are classified as high-grade B-cell lymphoma with MYC and BCL2 rearrangements ("double hit"; HGBCL-DH-BCL2) and are associated with aggressive disease and poor outcomes. Although it is established that MYC rearrangements involving immunoglobulin (IG) loci are associated with inferior outcomes relative to those involving other non-IG superenhancers, the frequency of and mechanisms driving IG vs non-IG MYC rearrangements have not been elucidated. Here, we used custom targeted capture and/or whole-genome sequencing to characterize oncogene rearrangements across 883 mature B-cell lymphomas including Burkitt lymphoma, follicular lymphoma, DLBCL, and HGBCL-DH-BCL2 tumors. We demonstrate that, although BCL2 rearrangement topology is consistent across entities, HGBCL-DH-BCL2 have distinct MYC rearrangement architecture relative to tumors with single MYC rearrangements or with both MYC and BCL6 rearrangements (HGBCL-DH-BCL6), including both a higher frequency of non-IG rearrangements and different architecture of MYC::IGH rearrangements. The distinct MYC rearrangement patterns in HGBCL-DH-BCL2 occur on the background of high levels of somatic hypermutation across MYC partner loci in HGBCL-DH-BCL2, creating more opportunity to form these rearrangements. Furthermore, because 1 IGH allele is already disrupted by the existing BCL2 rearrangement, the MYC rearrangement architecture in HGBCL-DH-BCL2 likely reflects selective pressure to preserve both BCL2 and B-cell receptor expression. These data provide new mechanistic explanations for the distinct patterns of MYC rearrangements observed across different lymphoma entities.
在成熟 B 细胞淋巴瘤中，癌基因 MYC、BCL2 或 BCL6 与超级增强子相邻的重排很常见。具有弥漫性大 B 细胞淋巴瘤（DLBCL）或高级形态学特征且同时存在 MYC 和 BCL2 重排的淋巴瘤被归类为具有 MYC 和 BCL2 重排的高级别 B 细胞淋巴瘤（HGBCL-DH-BCL2），并与侵袭性疾病和不良预后相关。尽管已经确定涉及免疫球蛋白（IG）基因座的 MYC 重排在预后方面相对于涉及其他非 IG 超级增强子的重排更差，但 IG 与非 IG MYC 重排的频率和驱动机制尚未阐明。在这里，我们使用定制的靶向捕获和/或全基因组测序来描述 883 例成熟 B 细胞淋巴瘤（包括伯基特淋巴瘤、滤泡性淋巴瘤、DLBCL 和 HGBCL-DH-BCL2 肿瘤）中的癌基因重排。我们证明，尽管 BCL2 重排拓扑在各实体中是一致的，但与具有单一 MYC 重排或同时具有 MYC 和 BCL6 重排的肿瘤（HGBCL-DH-BCL6）相比，HGBCL-DH-BCL2 具有独特的 MYC 重排结构，包括非 IG 重排的更高频率和 MYC::IGH 重排的不同结构。在 HGBCL-DH-BCL2 中，独特的 MYC 重排模式发生在 HGBCL-DH-BCL2 中 MYC 伙伴基因座的体细胞高频突变水平较高的背景下，从而为形成这些重排创造了更多机会。此外，由于 1 个 IGH 等位基因已经被现有 BCL2 重排破坏，因此 HGBCL-DH-BCL2 中的 MYC 重排结构可能反映了保留 BCL2 和 B 细胞受体表达的选择性压力。这些数据为不同淋巴瘤实体中观察到的不同 MYC 重排模式提供了新的机制解释。
