Journal Article

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

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

2026

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: ALL / BCR-ABL1 p190 / Cancer Research / Cell growth / Comparative analysis / Correspondence / CRISPR/Cas9 / DNA methylation / Epigenetics / Gene expression / Genes / Genetic research / Genomes / Hematology / Kinases / Leukemia / Medicine / Medicine & Public Health / Methylation / Oncology / Phenols / Philadelphia chromosome / Phosphorylation / Proteins / TKI sensitivity / Tyrosine / Y chromosomes