Variable behavior of iPSCs derived from CML patients for response to TKI and hematopoietic differentiation.
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.
Inserm U1035, Biothérapies des maladies génétiques et cancers, Bordeaux, France ; Université Bordeaux Segalen, Bordeaux, France.
Aurélie
A
Bedel
Jean-Max
JM
Pasquet
Eric
E
Lippert
Miguel
M
Taillepierre
Valérie
V
Lagarde
Sandrine
S
Dabernat
Pierre
P
Dubus
Lucie
L
Charaf
François
F
Beliveau
Hubert
H
de Verneuil
Emmanuel
E
Richard
François-Xavier
FX
Mahon
François
F
Moreau-Gaudry
D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors*; D006410:Hematopoiesis / Q000187:drug effects*; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000473:pathology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
C581634:BCR-ABL1 fusion protein, human; D047428:Protein Kinase Inhibitors; D016044:Fusion Proteins, bcr-abl