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PI3K/mTOR pathway inhibitors sensitize chronic myeloid leukemia stem cells to nilotinib and restore the response of progenitors to nilotinib in the presence of stem cell factor.

Airiau K, Mahon FX, Josselin M, Jeanneteau M, Belloc F - Cell Death Dis (2013)

Bottom Line: We previously demonstrated that nilotinib-induced apoptosis was reduced by stem cell factor (SCF) addition.However, this pathway seems not to be involved in the nilotinib-induced resistance of the CML stem cell population.Conversely, PI3K inhibition sensitized both CML progenitors and stem cells to nilotinib, suggesting that, downstream PI3K, two different kinase pathways are activated in CML progenitor and stem cell populations.

View Article: PubMed Central - PubMed

Affiliation: 1] Laboratoire d'Hématopoïèse Leucémique et Cibles Thérapeutiques, INSERM 1035, Université Bordeaux Segalen, 146 Rue Léo Saignat, Bordeaux Cedex 33076, France [2] CHU Bordeaux, Hôpital Haut-Lévêque, Laboratoire d'Hématologie, Avenue Magellan 33604 Pessac, France.

ABSTRACT
Nilotinib is a second-generation tyrosine kinase inhibitor, designed to specifically inhibit break-point cluster region (BCR)-Abelson (ABL) and developed to treat chronic myeloid leukemia (CML) in patients showing a resistance to imatinib. We previously demonstrated that nilotinib-induced apoptosis was reduced by stem cell factor (SCF) addition. Here, the SCF-activated survival pathway was investigated. BCR-ABL expression was accompanied by the activation of the SCF receptor: c-KIT. Nilotinib inhibited this activation that was restored by SCF binding. Parallel variations were observed for mammaliam target of rapamycin (mTOR) kinase and mTOR complex 1 substrate S6K. The inhibition of mTORC1 restored the response of BCR-ABL cell lines to nilotinib in the presence of SCF. PI3K inhibition restored nilotinib-induced apoptosis. On hematopoietic progenitors from CML patient's bone marrows, mTORC1 inhibition also restored nilotinib sensitivity in the presence of SCF, confirming its involvement in SCF-activated survival pathway. However, this pathway seems not to be involved in the nilotinib-induced resistance of the CML stem cell population. Conversely, PI3K inhibition sensitized both CML progenitors and stem cells to nilotinib, suggesting that, downstream PI3K, two different kinase pathways are activated in CML progenitor and stem cell populations.

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Related in: MedlinePlus

Survival pathways in CML progenitors and stem cells. In Bcr-Abl-expressing cell lines and CML progenitors, the binding of SCF to its receptor activates the PI3K pathway resulting in mTOR and Akt activation. In the absence of Bcr-Abl activity, the inhibition of mTOR is sufficient to induce cell death. In stem cells, survival is less dependent on the Bcr-Abl activity and was not affected by the mTOR inhibition. The activation of the c-kit/PI3K pathway is sufficient to sustain cell survival
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fig6: Survival pathways in CML progenitors and stem cells. In Bcr-Abl-expressing cell lines and CML progenitors, the binding of SCF to its receptor activates the PI3K pathway resulting in mTOR and Akt activation. In the absence of Bcr-Abl activity, the inhibition of mTOR is sufficient to induce cell death. In stem cells, survival is less dependent on the Bcr-Abl activity and was not affected by the mTOR inhibition. The activation of the c-kit/PI3K pathway is sufficient to sustain cell survival

Mentions: The upstream events leading to mTOR activation, following SCF binding, were investigated and it was found that the PI3K activity was implied. The mTOR inhibition was sufficient to overcome the protective effect of SCF on nilotinib-induced apoptosis in both CML cell lines and progenitors. However, it was inefficient to induce apoptosis in CD34+/CD38− CML cells which were also resistant to BCR-ABL inhibition.10, 28 Conversely, the PI3K inhibitors alone were able to induce apoptosis in CD34+/CD38−CML stem cells, illustrating different survival mechanisms in progenitors and stem cells (Figure 6). We observed that all the PI3K inhibitors tested were able to induce apoptosis by themselves in CML stem cells and this was increased after nilotinib addition, except for the dual PI3K/mTOR inhibitor BEZ-235. This last result suggests that, in a population for which BCR-ABL activity is not required by itself for the survival, nilotinib indirectly inhibited the mTOR kinase, explaining its inability to synergize with a dual PI3K/mTOR inhibitor, whereas it did synergize with PI3K inhibitors.


PI3K/mTOR pathway inhibitors sensitize chronic myeloid leukemia stem cells to nilotinib and restore the response of progenitors to nilotinib in the presence of stem cell factor.

Airiau K, Mahon FX, Josselin M, Jeanneteau M, Belloc F - Cell Death Dis (2013)

Survival pathways in CML progenitors and stem cells. In Bcr-Abl-expressing cell lines and CML progenitors, the binding of SCF to its receptor activates the PI3K pathway resulting in mTOR and Akt activation. In the absence of Bcr-Abl activity, the inhibition of mTOR is sufficient to induce cell death. In stem cells, survival is less dependent on the Bcr-Abl activity and was not affected by the mTOR inhibition. The activation of the c-kit/PI3K pathway is sufficient to sustain cell survival
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3824646&req=5

fig6: Survival pathways in CML progenitors and stem cells. In Bcr-Abl-expressing cell lines and CML progenitors, the binding of SCF to its receptor activates the PI3K pathway resulting in mTOR and Akt activation. In the absence of Bcr-Abl activity, the inhibition of mTOR is sufficient to induce cell death. In stem cells, survival is less dependent on the Bcr-Abl activity and was not affected by the mTOR inhibition. The activation of the c-kit/PI3K pathway is sufficient to sustain cell survival
Mentions: The upstream events leading to mTOR activation, following SCF binding, were investigated and it was found that the PI3K activity was implied. The mTOR inhibition was sufficient to overcome the protective effect of SCF on nilotinib-induced apoptosis in both CML cell lines and progenitors. However, it was inefficient to induce apoptosis in CD34+/CD38− CML cells which were also resistant to BCR-ABL inhibition.10, 28 Conversely, the PI3K inhibitors alone were able to induce apoptosis in CD34+/CD38−CML stem cells, illustrating different survival mechanisms in progenitors and stem cells (Figure 6). We observed that all the PI3K inhibitors tested were able to induce apoptosis by themselves in CML stem cells and this was increased after nilotinib addition, except for the dual PI3K/mTOR inhibitor BEZ-235. This last result suggests that, in a population for which BCR-ABL activity is not required by itself for the survival, nilotinib indirectly inhibited the mTOR kinase, explaining its inability to synergize with a dual PI3K/mTOR inhibitor, whereas it did synergize with PI3K inhibitors.

Bottom Line: We previously demonstrated that nilotinib-induced apoptosis was reduced by stem cell factor (SCF) addition.However, this pathway seems not to be involved in the nilotinib-induced resistance of the CML stem cell population.Conversely, PI3K inhibition sensitized both CML progenitors and stem cells to nilotinib, suggesting that, downstream PI3K, two different kinase pathways are activated in CML progenitor and stem cell populations.

View Article: PubMed Central - PubMed

Affiliation: 1] Laboratoire d'Hématopoïèse Leucémique et Cibles Thérapeutiques, INSERM 1035, Université Bordeaux Segalen, 146 Rue Léo Saignat, Bordeaux Cedex 33076, France [2] CHU Bordeaux, Hôpital Haut-Lévêque, Laboratoire d'Hématologie, Avenue Magellan 33604 Pessac, France.

ABSTRACT
Nilotinib is a second-generation tyrosine kinase inhibitor, designed to specifically inhibit break-point cluster region (BCR)-Abelson (ABL) and developed to treat chronic myeloid leukemia (CML) in patients showing a resistance to imatinib. We previously demonstrated that nilotinib-induced apoptosis was reduced by stem cell factor (SCF) addition. Here, the SCF-activated survival pathway was investigated. BCR-ABL expression was accompanied by the activation of the SCF receptor: c-KIT. Nilotinib inhibited this activation that was restored by SCF binding. Parallel variations were observed for mammaliam target of rapamycin (mTOR) kinase and mTOR complex 1 substrate S6K. The inhibition of mTORC1 restored the response of BCR-ABL cell lines to nilotinib in the presence of SCF. PI3K inhibition restored nilotinib-induced apoptosis. On hematopoietic progenitors from CML patient's bone marrows, mTORC1 inhibition also restored nilotinib sensitivity in the presence of SCF, confirming its involvement in SCF-activated survival pathway. However, this pathway seems not to be involved in the nilotinib-induced resistance of the CML stem cell population. Conversely, PI3K inhibition sensitized both CML progenitors and stem cells to nilotinib, suggesting that, downstream PI3K, two different kinase pathways are activated in CML progenitor and stem cell populations.

Show MeSH
Related in: MedlinePlus