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Phosphoprotein profiling predicts response to tyrosine kinase inhibitor therapy in chronic myeloid leukemia patients
Sari E Jalkanen1, Anna-Maria Lahesmaa-Korpinen, Caroline A Heckman
1Hematology Research Unit Helsinki, Department of Medicine, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
Abstract:
Tyrosine kinase inhibitors (TKIs) have dramatically improved treatment outcomes in chronic myeloid leukemia (CML), but a proportion of patients fail to achieve optimal molecular response. By using a phosphoproteomic approach, we aimed to discover aberrant signaling pathways and putative biomarkers in bone marrow samples of suboptimally responding patients, which could be used to guide treatment selection at the diagnosis. The study consisted of 20 chronic-phase CML patients (10 optimal and 10 suboptimal response patients based on 18 months European-Leukemia-Net criteria) and healthy bone marrow cells, and CML cell lines were used as controls. The phosphorylation profile of normal bone marrow cells diverged from CML patients expectedly but, interestingly, CML cell lines (such as K562) also showed marked difference with primary CML cells. Several phosphoproteins were elevated in suboptimal patients compared to optimal response group. Most prominent differences were seen in signal transducers and activators of transcription 5b, phospholipase C γ-1, proline-rich tyrosine kinase 2, Hck, and Paxillin. These phosphoproteins were also increased in three additional nonresponder patients studied, but each of them also had unique phosphorylation patterns, such as highly active HSP27 protein in one patient. In conclusion, suboptimal imatinib response is related to increased phosphorylation of several proteins at diagnosis, which might guide the selection of TKI therapy. Furthermore, the activation of additional BCR-ABL-independent pathways in nonresponder patients (such as the anti-apoptotic HSP27 pathway) may reveal novel therapy targets.
Insights
Suboptimal response to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) is linked to elevated phosphoprotein levels at diagnosis. Identifying these aberrant signaling pathways may guide future TKI treatment selection for CML patients.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Tyrosine kinase inhibitors (TKIs) have significantly improved chronic myeloid leukemia (CML) treatment outcomes.
- A subset of CML patients exhibit suboptimal molecular responses to TKIs, necessitating further investigation into underlying mechanisms.
Purpose of the Study:
- To identify aberrant signaling pathways and potential biomarkers in bone marrow samples from CML patients with suboptimal responses.
- To guide personalized TKI treatment selection at the time of diagnosis.
Main Methods:
- Phosphoproteomic analysis was performed on bone marrow samples from 20 chronic-phase CML patients (10 optimal, 10 suboptimal responders) and healthy controls.
- CML cell lines (e.g., K562) were utilized as additional controls to compare phosphorylation profiles.
Main Results:
- Distinct phosphorylation profiles were observed between normal bone marrow, CML patients, and CML cell lines.
- Elevated levels of specific phosphoproteins, including signal transducers and activators of transcription 5b (STAT5b), phospholipase C γ-1 (PLCγ1), proline-rich tyrosine kinase 2 (PYK2), Hck, and Paxillin, were identified in suboptimal responders.
- Additional nonresponder patients showed increased phosphoprotein levels, with unique patterns like highly active HSP27 in one case.
Conclusions:
- Suboptimal imatinib response in CML is associated with increased phosphorylation of specific proteins at diagnosis.
- Aberrant BCR-ABL-independent pathways, such as the anti-apoptotic HSP27 pathway, may represent novel therapeutic targets in TKI nonresponder CML patients.
