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Updated: May 7, 2026
Directed Differentiation of Induced Pluripotent Stem Cells towards T Lymphocytes
Published on: May 14, 2012
Variable behavior of iPSCs derived from CML patients for response to TKI and hematopoietic differentiation
Aurélie Bedel1, Jean-Max Pasquet, Eric Lippert
1Inserm U1035, Biothérapies des maladies génétiques et cancers, Bordeaux, France ; Université Bordeaux Segalen, Bordeaux, France.
Abstract:
Chronic myeloid leukemia disease (CML) found effective therapy by treating patients with tyrosine kinase inhibitors (TKI), which suppress the BCR-ABL1 oncogene activity. However, the majority of patients achieving remission with TKI still have molecular evidences of disease persistence. Various mechanisms have been proposed to explain the disease persistence and recurrence. One of the hypotheses is that the primitive leukemic stem cells (LSCs) can survive in the presence of TKI. Understanding the mechanisms leading to TKI resistance of the LSCs in CML is a critical issue but is limited by availability of cells from patients. We generated induced pluripotent stem cells (iPSCs) derived from CD34⁺ blood cells isolated from CML patients (CML-iPSCs) as a model for studying LSCs survival in the presence of TKI and the mechanisms supporting TKI resistance. Interestingly, CML-iPSCs resisted to TKI treatment and their survival did not depend on BCR-ABL1, as for primitive LSCs. Induction of hematopoietic differentiation of CML-iPSC clones was reduced compared to normal clones. Hematopoietic progenitors obtained from iPSCs partially recovered TKI sensitivity. Notably, different CML-iPSCs obtained from the same CML patients were heterogeneous, in terms of BCR-ABL1 level and proliferation. Thus, several clones of CML-iPSCs are a powerful model to decipher all the mechanisms leading to LSC survival following TKI therapy and are a promising tool for testing new therapeutic agents.
Insights
Induced pluripotent stem cells (iPSCs) from chronic myeloid leukemia (CML) patients reveal that leukemic stem cells (LSCs) resist tyrosine kinase inhibitors (TKI) independently of BCR-ABL1, offering a new model for TKI resistance research.
Area of Science:
- Hematology
- Stem Cell Biology
- Oncology
Background:
- Chronic myeloid leukemia (CML) is effectively treated with tyrosine kinase inhibitors (TKI) targeting the BCR-ABL1 oncogene.
- Despite TKI therapy, molecular evidence of disease persistence and recurrence suggests mechanisms of resistance.
- Leukemic stem cells (LSCs) are hypothesized to survive TKI treatment, contributing to disease persistence.
Purpose of the Study:
- To develop a model for studying TKI resistance in CML leukemic stem cells (LSCs).
- To investigate the mechanisms underlying LSC survival during TKI therapy.
- To utilize induced pluripotent stem cells (iPSCs) from CML patients (CML-iPSCs) as a research model.
Main Methods:
- Generation of CML-iPSCs from CD34+ blood cells of CML patients.
- Assessment of TKI resistance and BCR-ABL1 dependency in CML-iPSCs.
- Evaluation of hematopoietic differentiation capacity and TKI sensitivity of derived progenitors.
- Analysis of heterogeneity among different CML-iPSC clones from the same patient.
Main Results:
- CML-iPSCs exhibited resistance to TKI treatment, independent of BCR-ABL1.
- Hematopoietic differentiation was reduced in CML-iPSC clones compared to normal controls.
- Hematopoietic progenitors derived from CML-iPSCs showed partial recovery of TKI sensitivity.
- Significant heterogeneity was observed among CML-iPSC clones regarding BCR-ABL1 levels and proliferation.
Conclusions:
- CML-iPSCs provide a powerful model to study TKI resistance mechanisms in LSCs.
- LSC survival in TKI therapy involves BCR-ABL1-independent pathways.
- CML-iPSC clones are a valuable tool for exploring therapeutic strategies against TKI resistance.
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