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大规模的染色体区域 9 和 22 的拓扑结构破坏与 CML 治疗无反应相关。

Large-scale topological disruption of chromosome territories 9 and 22 is associated with nonresponse to treatment in CML.

机构信息

Doctorado en Ciencias Biomédicas, Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico.

Unidad de Aplicaciones Avanzadas en Microscopía (ADMiRA), Instituto Nacional de Cancerología (INCan), Red de Apoyo a la Investigación (RAI), Universidad Nacional Autónoma de México (UNAM), Mexico City, Mexico.

出版信息

Int J Cancer. 2022 May 1;150(9):1455-1470. doi: 10.1002/ijc.33903. Epub 2021 Dec 29.

DOI:10.1002/ijc.33903
PMID:34913480
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9303775/
Abstract

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm defined by the presence of t(9;22) translocation whose origin has been associated with the tridimensional genome organization. This rearrangement leads to the fusion of BCR and ABL1 genes giving rise to a chimeric protein with constitutive kinase activity. Imatinib, a tyrosine kinase inhibitor (TKI), is used as a first-line treatment for CML, though ~40% of CML patients do not respond. Here, using structured illumination microscopy (SIM) and 3D reconstruction, we studied the 3D organization patterns of the ABL1 and BCR genes, and their chromosome territories (CTs) CT9 and CT22, in CD34+ cells from CML patients that responded or not to TKI. We found that TKI resistance in CML is associated with high levels of structural disruption of CT9 and CT22 in CD34+ cells, increased CT volumes (especially for CT22), intermingling between CT9 and CT22, and an open-chromatin epigenetic mark in CT22. Altogether our results suggest that large-scale disruption of CT9 and CT22 correlates with the clinical response of CML patients, which could be translated into a potential prognostic marker of response to treatment in this disease and provide novel insights into the mechanisms underlying resistance to TKI in CML.

摘要

慢性髓性白血病（CML）是一种骨髓增生性肿瘤，其特征是存在 t（9；22）易位，其起源与三维基因组组织有关。这种重排导致 BCR 和 ABL1 基因融合，产生具有组成性激酶活性的嵌合蛋白。伊马替尼是一种酪氨酸激酶抑制剂（TKI），被用作 CML 的一线治疗药物，但约 40%的 CML 患者对此没有反应。在这里，我们使用结构照明显微镜（SIM）和 3D 重建技术，研究了 TKI 反应或不反应的 CML 患者 CD34+细胞中 ABL1 和 BCR 基因及其染色体区室（CT）CT9 和 CT22 的 3D 组织模式。我们发现，CML 中的 TKI 耐药与 CD34+细胞中 CT9 和 CT22 的结构破坏程度高、CT 体积增加（尤其是 CT22）、CT9 和 CT22 之间的混合以及 CT22 中的开放染色质表观遗传标记有关。总的来说，我们的结果表明，CT9 和 CT22 的大规模破坏与 CML 患者的临床反应相关，这可能转化为该疾病对治疗反应的潜在预后标志物，并为 CML 中对 TKI 耐药的机制提供新的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c63/9303775/73e3a33f8ddc/IJC-150-1455-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c63/9303775/af1603b47831/IJC-150-1455-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c63/9303775/d72471efa923/IJC-150-1455-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c63/9303775/291853fafcab/IJC-150-1455-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c63/9303775/c209a9bf8dae/IJC-150-1455-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c63/9303775/73e3a33f8ddc/IJC-150-1455-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c63/9303775/af1603b47831/IJC-150-1455-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c63/9303775/d72471efa923/IJC-150-1455-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c63/9303775/291853fafcab/IJC-150-1455-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c63/9303775/c209a9bf8dae/IJC-150-1455-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4c63/9303775/73e3a33f8ddc/IJC-150-1455-g005.jpg

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