威康桑格研究所Jyoti Nangalia研究团队在研究中取得进展。他们的最新研究提出了BCR的时间和轨迹：ABL1驱动的慢性髓系白血病。这一研究成果于2025年4月9日发表在国际顶尖学术期刊《自然》上。

对9例22 ~ 81岁CML患者的1013个造血集落进行全基因组测序多年来，研究团队重建了造血系统发育树。BCR和ABL1中的内含子断裂并不总是被观察到，BCR中的外显子断点也被注意到，需要外显子跳跃来推导BCR::ABL1。除了ASXL1和RUNX1突变外，额外的髓系基因突变主要存在于野生型细胞中。该研究组推断BCR: ABL1的爆炸性增长将从3-14年开始。诊断前几年（置信区间2-16年），年增长率超过每年70,000%。端粒长度较短的BCR::ABL1细胞的突变积累较高，反映了它们过度的细胞分裂。克隆扩增率与诊断时间呈负相关。一般人群中的BCR::ABL1反映了CML的发病率，晚期和/或爆炸期CML的特征是随后的基因组进化。这些数据强调了BCR::ABL1基因的致癌能力，并与大多数癌症缓慢和顺序的克隆轨迹形成对比。

据悉，一些基因的突变导致不受控制的细胞增殖和癌症。慢性髓性白血病（CML）中的费城染色体首次提供了这种与癌症的遗传联系。然而，对于CML的发展轨迹、BCR::ABL1克隆扩增率及其对疾病的影响知之甚少。

附：英文原文

Title: Timing and trajectory of BCR::ABL1-driven chronic myeloid leukaemia

Author: Kamizela, Aleksandra E., Leongamornlert, Daniel, Williams, Nicholas, Wang, Xin, Nyamondo, Kudzai, Dawson, Kevin, Spencer Chapman, Michael, Guo, Jing, Lee, Joe, Mane, Karim, Milne, Kate, Green, Anthony R., Chevassut, Timothy, Campbell, Peter J., Ellinor, Patrick T., Huntly, Brian J. P., Baxter, E. Joanna, Nangalia, Jyoti

Issue&Volume: 2025-04-09

Abstract: Mutation of some genes drives uncontrolled cell proliferation and cancer. The Philadelphia chromosome in chronic myeloid leukaemia (CML) provided the very first such genetic link to cancer1,2. However, little is known about the trajectory to CML, the rate of BCR::ABL1 clonal expansion and how this affects disease. Using whole-genome sequencing of 1,013 haematopoietic colonies from nine patients with CML aged 22 to 81years, we reconstruct phylogenetic trees of haematopoiesis. Intronic breaks in BCR and ABL1 were not always observed, and out-of-frame exonic breakpoints in BCR, requiring exon skipping to derive BCR::ABL1, were also noted. Apart from ASXL1 and RUNX1 mutations, extra myeloid gene mutations were mostly present in wild-type cells. We inferred explosive growth attributed to BCR::ABL1 commencing 3–14years (confidence interval 2–16years) before diagnosis, with annual growth rates exceeding 70,000% per year. Mutation accumulation was higher in BCR::ABL1 cells with shorter telomere lengths, reflecting their excessive cell divisions. Clonal expansion rates inversely correlated with the time to diagnosis. BCR::ABL1 in the general population mirrored CML incidence, and advanced and/or blast phase CML was characterized by subsequent genomic evolution. These data highlight the oncogenic potency of BCR::ABL1 fusion and contrast with the slow and sequential clonal trajectories of most cancers.

DOI: 10.1038/s41586-025-08817-2

Source: https://www.nature.com/articles/s41586-025-08817-2