PTEN is indispensable for cells to respond to MAPK inhibitors in myeloid leukemia
Jingliao Zhang1, Zhifu Xiang2, Priyangi A Malaviarachchi2
1Winthrop P. Rockefeller Cancer Institute, Division of Hematology, Department of Internal Medicine, College of Medicine, University of Arkansas for Medical Sciences (UAMS), Little Rock, AR 72205, United States; Department of Pediatrics, Institute of Hematology and Blood Disease Hospital, Chinese Academy of Medical Sciences, Tianjin 300020, China.
Abstract:
Constitutively activated MAPK and AKT signaling pathways are often found in solid tumors and leukemias. PTEN is one of the tumor suppressors that are frequently found deficient in patients with late-stage cancers or leukemias. In this study we demonstrate that a MAPK inhibitor, PD98059, inhibits both AKT and ERK phosphorylation in a human myeloid leukemia cell line (TF-1), but not in PTEN-deficient leukemia cells (TF-1a). Ectopic expression of wild-type PTEN in myeloid leukemia cells restored cytokine responsiveness at physiological concentrations of GM-CSF (<0.02 ng/mL) and significantly improved cell sensitivity to MAPK inhibitor. We also found that Early Growth Response 1 (EGR1) was constitutively over-expressed in cytokine-independent TF-1a cells, and ectopic expression of PTEN down-regulated EGR1 expression and restored dynamics of EGR1 expression in response to GM-CSF stimulation. Data from primary bone marrow cells from mice with Pten deletion further supports that PTEN is indispensible for myeloid leukemia cells in response to MAPK inhibitors. Finally, We demonstrate that the absence of EGR1 expression dynamics in response to GM-CSF stimulation is one of the mechanisms underlying drug resistance to MAPK inhibitors in leukemia cells with PTEN deficiency. Our data suggest a novel mechanism of PTEN in regulating expression of EGR1 in hematopoietic cells in response to cytokine stimulation. In conclusion, this study demonstrates that PTEN is dispensable for myeloid leukemia cells in response to MAPK inhibitors, and PTEN regulates EGR1 expression and contributes to the cytokine sensitivity in leukemia cells.
Insights
Phosphatase and tensin homolog (PTEN) deficiency in leukemia cells causes resistance to MAPK inhibitors. Restoring PTEN re-sensitizes cells by regulating Early Growth Response 1 (EGR1) expression and cytokine sensitivity.
Area of Science:
- Oncology
- Molecular Biology
- Hematology
Background:
- Constitutively activated MAPK and AKT signaling pathways are implicated in various cancers, including leukemia.
- PTEN, a crucial tumor suppressor, is frequently lost in advanced cancers and leukemias, contributing to disease progression.
- PTEN deficiency is linked to resistance against targeted therapies, necessitating a deeper understanding of its role in drug response.
Purpose of the Study:
- To investigate the role of PTEN in regulating sensitivity to MAPK inhibitors in myeloid leukemia.
- To elucidate the molecular mechanisms by which PTEN influences drug resistance in leukemia cells.
- To explore the relationship between PTEN, Early Growth Response 1 (EGR1), and cytokine signaling in leukemia.
Main Methods:
- Utilized human myeloid leukemia cell lines (TF-1 and PTEN-deficient TF-1a) to assess responses to MAPK inhibitor PD98059.
- Employed ectopic expression of wild-type PTEN to restore its function in deficient cells.
- Analyzed gene expression of EGR1 and cytokine responsiveness (GM-CSF) in response to PTEN manipulation and drug treatment.
- Examined primary bone marrow cells from Pten-deleted mice to validate findings in a more complex system.
Main Results:
- MAPK inhibitor PD98059 inhibited AKT and ERK phosphorylation in PTEN-wild-type cells but not in PTEN-deficient cells.
- Ectopic PTEN expression restored GM-CSF responsiveness and enhanced sensitivity to MAPK inhibitors.
- Constitutive EGR1 overexpression in PTEN-deficient cells was down-regulated by PTEN, restoring EGR1 dynamics with GM-CSF.
- PTEN deletion in mouse myeloid cells confirmed its essential role in response to MAPK inhibitors.
Conclusions:
- PTEN is critical for myeloid leukemia cell sensitivity to MAPK inhibitors.
- PTEN regulates EGR1 expression, influencing cytokine sensitivity and drug response in leukemia.
- Dysregulation of EGR1 expression dynamics due to PTEN deficiency is a key mechanism of MAPK inhibitor resistance in leukemia.
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