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CAMKIIγ, HSP70 and HSP90 transcripts are differentially expressed in chronic myeloid leukemia cells from patients
Mariana Gonzalez1, Carlos De Brasi, Cristian Ferri
1Instituto de Medicina Experimental (IMEX, CONICET-ANM).
Abstract:
Patients with chronic myeloid leukemia (CML) can develop disease resistance to tyrosine kinase inhibitor (TKI) therapy, which is mainly attributable to the presence of point mutations in the tyrosine kinase domain of BCR-ABL1. In order to examine suitable markers to monitor treatment efficacy, we investigated transcript expression profiles of genes known to be involved in myeloid cell proliferation, such as CAMKIIγ and KI67, and in protein stability and ultimately cell survival under physiological and stress conditions, such as heat shock proteins HSP70 and HSP90. We studied 101 patients with CML in different stages of disease and with different responses to TKI treatment. The results of quantitative real-time polymerase chain reaction (qPCR) analyses showed that the expression levels of CAMKIIγ, KI67, HSP70 and HSP90 genes were up-regulated at diagnosis, and in cases with signs of treatment resistance both in chronic and advanced phases (accelerated and blastic phases) with respect to chronic phase in remission and healthy donors. When only 56 resistant cases, 31 with mutations (MT) and 25 without mutations (WT), in the BCR-ABL1 tyrosine kinase domain were considered, the transcript expression profile showed an unexpected significant increase in CAMKIIγ and HSP70, and a significant decrease in HSP90 in MT versus WT cases. This differential transcript expression prompted us to design an expression score, log(CAMKIIγ × HSP70/HSP90), which can be used to provide rapid screening to discriminate the presence or absence of mutations in resistant cells and to monitor TKI treatment efficacy in patients with CML.
Insights
Researchers identified gene expression markers to monitor chronic myeloid leukemia (CML) treatment resistance. An expression score using CAMKIIγ, HSP70, and HSP90 can help detect BCR-ABL1 mutations and assess TKI therapy effectiveness.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Chronic myeloid leukemia (CML) treatment resistance to tyrosine kinase inhibitors (TKIs) often arises from BCR-ABL1 mutations.
- Monitoring treatment efficacy and detecting resistance mechanisms are crucial for CML patient management.
Purpose of the Study:
- To investigate transcript expression profiles of specific genes as potential biomarkers for CML treatment response.
- To develop a method for rapid screening of BCR-ABL1 mutations and monitoring TKI therapy efficacy in CML patients.
Main Methods:
- Quantitative real-time polymerase chain reaction (qPCR) was used to analyze gene expression in 101 CML patients.
- Expression levels of CAMKIIγ, KI67, HSP70, and HSP90 were assessed at diagnosis and during TKI treatment.
- An expression score, log(CAMKIIγ × HSP70/HSP90), was derived to differentiate mutation status.
Main Results:
- CAMKIIγ, KI67, HSP70, and HSP90 gene expression was elevated at diagnosis and in TKI-resistant CML cases.
- In TKI-resistant patients, mutation-positive (MT) cases showed significantly higher CAMKIIγ and HSP70, and lower HSP90 compared to mutation-negative (WT) cases.
- The developed expression score effectively distinguished between MT and WT BCR-ABL1 tyrosine kinase domains.
Conclusions:
- CAMKIIγ, HSP70, and HSP90 transcript levels serve as potential biomarkers for CML progression and TKI resistance.
- The novel expression score offers a promising tool for rapid mutation screening and monitoring TKI treatment efficacy in CML.
- This approach may aid in personalized treatment strategies for CML patients.
