转录因子 IKZF3 中的热点突变通过转录失调驱动 B 细胞肿瘤发生。
A hotspot mutation in transcription factor IKZF3 drives B cell neoplasia via transcriptional dysregulation.
机构信息
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; INSERM, U978, Université Paris 13, Bobigny, France; Laboratoire d'Hématologie, APHP Hôpital Avicenne, Bobigny, France.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
出版信息
Cancer Cell. 2021 Mar 8;39(3):380-393.e8. doi: 10.1016/j.ccell.2021.02.003.
Hotspot mutation of IKZF3 (IKZF3-L162R) has been identified as a putative driver of chronic lymphocytic leukemia (CLL), but its function remains unknown. Here, we demonstrate its driving role in CLL through a B cell-restricted conditional knockin mouse model. Mutant Ikzf3 alters DNA binding specificity and target selection, leading to hyperactivation of B cell receptor (BCR) signaling, overexpression of nuclear factor κB (NF-κB) target genes, and development of CLL-like disease in elderly mice with a penetrance of ~40%. Human CLL carrying either IKZF3 mutation or high IKZF3 expression was associated with overexpression of BCR/NF-κB pathway members and reduced sensitivity to BCR signaling inhibition by ibrutinib. Our results thus highlight IKZF3 oncogenic function in CLL via transcriptional dysregulation and demonstrate that this pro-survival function can be achieved by either somatic mutation or overexpression of this CLL driver. This emphasizes the need for combinatorial approaches to overcome IKZF3-mediated BCR inhibitor resistance.
IKZF3（IKZF3-L162R）热点突变已被确定为慢性淋巴细胞白血病（CLL）的潜在驱动因素，但它的功能仍不清楚。在这里，我们通过 B 细胞限制性条件敲入小鼠模型证明了其在 CLL 中的驱动作用。突变 Ikzf3 改变了 DNA 结合特异性和靶标选择，导致 B 细胞受体（BCR）信号的过度激活、核因子 κB（NF-κB）靶基因的过度表达，并导致老年小鼠中出现类似 CLL 的疾病，其外显率约为 40%。携带 IKZF3 突变或 IKZF3 高表达的人类 CLL 与 BCR/NF-κB 通路成员的过度表达以及对伊布替尼抑制 BCR 信号的敏感性降低有关。因此，我们的研究结果突出了 IKZF3 通过转录失调在 CLL 中的致癌功能，并证明这种生存促进功能可以通过体细胞突变或该 CLL 驱动基因的过表达来实现。这强调了需要采用联合方法来克服 IKZF3 介导的 BCR 抑制剂耐药性。
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