Scholarlink

<p>The Philadelphia chromosome is the result of a balanced reciprocal translocation between the long arms of chromosomes 9 and 22, resulting in the fusion gene BCR-ABL1. Despite it being a hallmark of acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML) and mixed-phenotype acute leukemia, comparatively little is known about its effects, which can be directly attributed to its presence in cancer cells. To study this question, we created and characterized a Jurkat cell line carrying this alteration via a CRISPR/Cas9-based approach. Compared with wild-type Jurkat cells, BCR-ABL1 p190-expressing cells exhibited increased proliferation and increased sensitivity to tyrosine kinase inhibitors (TKIs). By integrating gene expression, DNA methylation and protein expression data generated by next-generation sequencing (NGS) and mass spectrometry analyses, we identified a number of pathways as well as individual proteins that are altered in association with BCR-ABL1 p190. Among the deregulated proteins, we identified known cancer proteins, such as the tumor suppressors ASS1 and ABI3, which were downregulated in our model, or specifically upregulated TRBC1. Particularly noteworthy is the downregulation of CYP51A1, which is known to confer TKI resistance under normal circumstances, and therefore directly associated with increased TKI sensitivity in BCR-ABL1 p190-positive cells. Another interesting feature is SPART, whose abundance was increased despite strong promoter hypermethylation, indicating that some transcriptional changes in BCR-ABL1 p190-carrying cells occur independently of promoter methylation and reflect broader regulatory effects of the fusion.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Molecular background of Philadelphia chromosome dependent enhancement of cellular growth and tyrosine kinase inhibitor sensitivity

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月19日

查看全文
  • Md Faruq Hossain,
  • Lisa Hagenau,
  • Lars R. Jensen,
  • Johannes Rhode,
  • Thomas Sura,
  • Manuela G. Salazar,
  • Ana Tzvetkova,
  • Corinna Jensen,
  • Stephanie Edwards,
  • Heiko Dunkel,
  • Stefan Simm,
  • Josefine Radke,
  • Andreas W. Kuss

摘要

The Philadelphia chromosome is the result of a balanced reciprocal translocation between the long arms of chromosomes 9 and 22, resulting in the fusion gene BCR-ABL1. Despite it being a hallmark of acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML) and mixed-phenotype acute leukemia, comparatively little is known about its effects, which can be directly attributed to its presence in cancer cells. To study this question, we created and characterized a Jurkat cell line carrying this alteration via a CRISPR/Cas9-based approach. Compared with wild-type Jurkat cells, BCR-ABL1 p190-expressing cells exhibited increased proliferation and increased sensitivity to tyrosine kinase inhibitors (TKIs). By integrating gene expression, DNA methylation and protein expression data generated by next-generation sequencing (NGS) and mass spectrometry analyses, we identified a number of pathways as well as individual proteins that are altered in association with BCR-ABL1 p190. Among the deregulated proteins, we identified known cancer proteins, such as the tumor suppressors ASS1 and ABI3, which were downregulated in our model, or specifically upregulated TRBC1. Particularly noteworthy is the downregulation of CYP51A1, which is known to confer TKI resistance under normal circumstances, and therefore directly associated with increased TKI sensitivity in BCR-ABL1 p190-positive cells. Another interesting feature is SPART, whose abundance was increased despite strong promoter hypermethylation, indicating that some transcriptional changes in BCR-ABL1 p190-carrying cells occur independently of promoter methylation and reflect broader regulatory effects of the fusion.