Centre de Référence Maladies Rares

U1035 INSERM

Biotherapy of genetic diseases, inflammatory disorders and cancers (BMGIC)

FR: Biologie Fondamentale Appliquée à la Médecine

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Biotherapy team
Project 1.4

CML stem cells : IPSCs approach

keywords: CML, cancer stem cell, TKI resistance, iPSC

Description:

Although tyrosine kinase inhibitors (TKIs) efficiently cure chronic myeloid leukemia (CML), they can fail to eradicate CML stem cells (CML-SCs). The mechanisms responsible for CML-SC survival need to be understood for designing therapies. Several previous studies suggest that TKIs could modulate CML-SC quiescence. Unfortunately, CML-SCs are insufficiently available. Induced pluripotent stem cells (iPSCs) offer a promising alternative. In this work, we used iPSCs derived from CML patients (Ph+). Ph+ iPSC clones expressed lower levels of stemness markers than normal iPSCs. BCR–ABL1 was found to be involved in stemness regulation and ERK1/2 to have a key role in the signaling pathway. TKIs unexpectedly promoted stemness marker expression in Ph+ iPSC clones. Imatinib also retained quiescence and induced stemness gene expression in CML-SCs. Our results suggest that TKIs might have a role in residual disease and confirm the need for a targeted therapy different from TKIs that could overcome the stemness promoting effect caused by TKIs. Interestingly, a similar pro-stemness effect was observed in normal iPSCs and hematopoietic SCs. These findings could help to explain CML resistance mechanisms and the teratogenic side-effects of TKIs in embryonic cells.

Related publications:

  • Effect of tyrosine kinase inhibitors on stemness in normal and chronic myeloid leukemia cells. Charaf L, Mahon FX, Lamrissi-Garcia I, Moranvillier I, Beliveau F, Cardinaud B, Dabernat S, de Verneuil H, Moreau-Gaudry F * , Bedel A Leukemia. (2017-01) doi: 10.1038/leu.2016.154.
  • What are the challenges in 2016 regarding resistance to TKI in CML and cancers? Lewis M, Copland M, Soverini S, Sadovnik I, Bedel A, Prost S, Italiano A, Mahon FX Hematological Oncology, (2016-07-19) 10.1002/hon.2329.
  • Variable behavior of iPSCs derived from CML patients for response to TKI and hematopoietic differentiation. Bedel A, Pasquet JM, Lippert E, Taillepierre M, Lagarde V, Dabernat S, Dubus P, Charaf L, Beliveau F, de Verneuil H, Richard E, Mahon FX, Moreau-Gaudry F. PLoS One (2013-08) doi: 10.1371/journal.pone.007159

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INSERM U1035! - University of Bordeaux
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