Davies Nicholas J, Kwok Marwan, Gould Clive, Oldreive Ceri E, Mao Jingwen, Parry Helen, Smith Edward, Agathanggelou Angelo, Pratt Guy, Taylor Alexander Malcolm R, Moss Paul, Griffiths Mike, Stankovic Tatjana
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
West Midlands Regional Genetics Laboratory, Birmingham Women's NHS Foundation Trust, Birmingham, UK.
Oncotarget. 2017 Jul 4;8(27):44749-44760. doi: 10.18632/oncotarget.17432.
Subclonal heterogeneity and clonal selection influences disease progression in chronic lymphocytic leukemia (CLL). It is therefore important that therapeutic decisions are made based on an understanding of the CLL clonal architecture and its dynamics in individual patients. Identification of cytogenetic abnormalities by FISH remains the cornerstone of contemporary clinical practice and provides a simple means for prognostic stratification. Here, we demonstrate that multiplexed-FISH can enhance recognition of CLL subclonal repertoire and its dynamics during disease progression, both in patients and CLL patient-derived xenografts (PDX). We applied a combination of patient-specific FISH probes to 24 CLL cases before treatment and at relapse, and determined putative ancestral relationships between subpopulations with different cytogenetic features. We subsequently established 7 CLL PDX models in NOD/Shi-SCID/IL-2Rγctm1sug/Jic (NOG) mice. Application of multiplexed-FISH to these models demonstrated that all of the identified cytogenetic subpopulations had leukemia propagating activity and that changes in their representation during disease progression could be spontaneous, accelerated by treatment or treatment-induced. We conclude that multiplexed-FISH in combination with PDX models have the potential to distinguish between spontaneous and treatment-induced clonal selection, and therefore provide a valuable tool for the pre-clinical evaluation of novel therapies.
亚克隆异质性和克隆选择影响慢性淋巴细胞白血病（CLL）的疾病进展。因此，基于对个体患者CLL克隆结构及其动态变化的了解来做出治疗决策非常重要。通过荧光原位杂交（FISH）鉴定细胞遗传学异常仍然是当代临床实践的基石，并为预后分层提供了一种简单方法。在此，我们证明多重FISH可以增强对CLL亚克隆组成及其在疾病进展过程中的动态变化的识别，无论是在患者还是CLL患者来源的异种移植（PDX）中。我们将患者特异性FISH探针组合应用于24例CLL患者治疗前和复发时的病例，并确定了具有不同细胞遗传学特征的亚群之间的推定祖先关系。随后，我们在NOD/Shi-SCID/IL-2Rγctm1sug/Jic（NOG）小鼠中建立了7个CLL PDX模型。将多重FISH应用于这些模型表明，所有鉴定出的细胞遗传学亚群都具有白血病增殖活性，并且它们在疾病进展过程中的比例变化可能是自发的、由治疗加速或由治疗诱导的。我们得出结论，多重FISH与PDX模型相结合有潜力区分自发和治疗诱导的克隆选择，因此为新疗法的临床前评估提供了一个有价值的工具。
