The molecular background of Philadelphia Chromosome-dependent enhancement of cellular growth and tyrosine kinase inhibitor sensitivity
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, still comparatively little is known about effects that can be directly attributed to its presence in cancer cells. In order to study this question, we have created and characterised a Jurkat cell line with such an alteration, using a CRISPR/Cas9 based approach. The BCR-ABL1 p190 carrying cells showed increased proliferation as well as elevated sensitivity towards tyrosine kinase inhibitors (TKIs) compared to wild type Jurkat cells. By integrating gene expression, DNA-methylation and protein expression data, generated by NGS and mass spectrometry analyses, we identified a number of pathways as well as individual proteins that show specific responses to the presence of BCR-ABL1 p190. Among the deregulated proteins we found known cancer proteins such as the tumor suppressors ASS1 and ABI3, which were downregulated in our model, or the specifically upregulated TRBC1. Particularly noteworthy is the downregulation of CYP51A1 which is known to confer TKI-resistance under normal circumstances and is therefore directly in line with the increased TKI sensitivity of our BCR-ABL1 p190 positive cells. Also of interest is SPART, whose abundance in our model was increased despite strong promoter hypermethylation, illustrating that some transcriptional changes in BCR-ABL1 p190 carrying cells occur independently of promoter methylation and reflect broader regulatory effects of the fusion