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Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells

Bellodi, Cristian LU ; Lidonnici, Maria Rosa ; Hamilton, Ashley ; Helgason, G Vignir ; Soliera, Angela Rachele ; Ronchetti, Mattia ; Galavotti, Sara ; Young, Kenneth W ; Selmi, Tommaso and Yacobi, Rinat , et al. (2009) In Journal of Clinical Investigation 119(5). p.23-1109
Abstract

Imatinib mesylate (IM), a potent inhibitor of the BCR/ABL tyrosine kinase, has become standard first-line therapy for patients with chronic myeloid leukemia (CML), but the frequency of resistance increases in advancing stages of disease. Elimination of BCR/ABL-dependent intracellular signals triggers apoptosis, but it is unclear whether this activates additional cell survival and/or death pathways. We have shown here that IM induces autophagy in CML blast crisis cell lines, CML primary cells, and p210BCR/ABL-expressing myeloid precursor cells. IM-induced autophagy did not involve c-Abl or Bcl-2 activity but was associated with ER stress and was suppressed by depletion of intracellular Ca2+, suggesting it is mechanistically... (More)

Imatinib mesylate (IM), a potent inhibitor of the BCR/ABL tyrosine kinase, has become standard first-line therapy for patients with chronic myeloid leukemia (CML), but the frequency of resistance increases in advancing stages of disease. Elimination of BCR/ABL-dependent intracellular signals triggers apoptosis, but it is unclear whether this activates additional cell survival and/or death pathways. We have shown here that IM induces autophagy in CML blast crisis cell lines, CML primary cells, and p210BCR/ABL-expressing myeloid precursor cells. IM-induced autophagy did not involve c-Abl or Bcl-2 activity but was associated with ER stress and was suppressed by depletion of intracellular Ca2+, suggesting it is mechanistically nonoverlapping with IM-induced apoptosis. We further demonstrated that suppression of autophagy using either pharmacological inhibitors or RNA interference of essential autophagy genes enhanced cell death induced by IM in cell lines and primary CML cells. Critically, the combination of a tyrosine kinase inhibitor (TKI), i.e., IM, nilotinib, or dasatinib, with inhibitors of autophagy resulted in near complete elimination of phenotypically and functionally defined CML stem cells. Together, these findings suggest that autophagy inhibitors may enhance the therapeutic effects of TKIs in the treatment of CML.

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type
Contribution to journal
publication status
published
subject
keywords
Animals, Antineoplastic Agents, Autophagy, Benzamides, Calcium, Cell Death, Cell Line, Tumor, Chloroquine, Dasatinib, Endoplasmic Reticulum, Fusion Proteins, bcr-abl, Gene Expression, Humans, Imatinib Mesylate, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Macrolides, Mice, Mice, Inbred C3H, Microtubule-Associated Proteins, Neoplastic Stem Cells, Piperazines, Protein Kinase Inhibitors, Protein-Tyrosine Kinases, Pyrimidines, RNA Interference, Thiazoles, Transcription Factor CHOP, Xenograft Model Antitumor Assays
in
Journal of Clinical Investigation
volume
119
issue
5
pages
15 pages
publisher
The American Society for Clinical Investigation
external identifiers
  • pmid:19363292
  • scopus:66449122303
ISSN
0021-9738
DOI
10.1172/JCI35660
language
English
LU publication?
no
id
e3f8c9d4-a865-4225-ae96-a35bbc73dde0
date added to LUP
2016-04-29 15:59:18
date last changed
2024-04-18 23:16:17
@article{e3f8c9d4-a865-4225-ae96-a35bbc73dde0,
  abstract     = {{<p>Imatinib mesylate (IM), a potent inhibitor of the BCR/ABL tyrosine kinase, has become standard first-line therapy for patients with chronic myeloid leukemia (CML), but the frequency of resistance increases in advancing stages of disease. Elimination of BCR/ABL-dependent intracellular signals triggers apoptosis, but it is unclear whether this activates additional cell survival and/or death pathways. We have shown here that IM induces autophagy in CML blast crisis cell lines, CML primary cells, and p210BCR/ABL-expressing myeloid precursor cells. IM-induced autophagy did not involve c-Abl or Bcl-2 activity but was associated with ER stress and was suppressed by depletion of intracellular Ca2+, suggesting it is mechanistically nonoverlapping with IM-induced apoptosis. We further demonstrated that suppression of autophagy using either pharmacological inhibitors or RNA interference of essential autophagy genes enhanced cell death induced by IM in cell lines and primary CML cells. Critically, the combination of a tyrosine kinase inhibitor (TKI), i.e., IM, nilotinib, or dasatinib, with inhibitors of autophagy resulted in near complete elimination of phenotypically and functionally defined CML stem cells. Together, these findings suggest that autophagy inhibitors may enhance the therapeutic effects of TKIs in the treatment of CML.</p>}},
  author       = {{Bellodi, Cristian and Lidonnici, Maria Rosa and Hamilton, Ashley and Helgason, G Vignir and Soliera, Angela Rachele and Ronchetti, Mattia and Galavotti, Sara and Young, Kenneth W and Selmi, Tommaso and Yacobi, Rinat and Van Etten, Richard A and Donato, Nick and Hunter, Ann and Dinsdale, David and Tirrò, Elena and Vigneri, Paolo and Nicotera, Pierluigi and Dyer, Martin J and Holyoake, Tessa and Salomoni, Paolo and Calabretta, Bruno}},
  issn         = {{0021-9738}},
  keywords     = {{Animals; Antineoplastic Agents; Autophagy; Benzamides; Calcium; Cell Death; Cell Line, Tumor; Chloroquine; Dasatinib; Endoplasmic Reticulum; Fusion Proteins, bcr-abl; Gene Expression; Humans; Imatinib Mesylate; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Macrolides; Mice; Mice, Inbred C3H; Microtubule-Associated Proteins; Neoplastic Stem Cells; Piperazines; Protein Kinase Inhibitors; Protein-Tyrosine Kinases; Pyrimidines; RNA Interference; Thiazoles; Transcription Factor CHOP; Xenograft Model Antitumor Assays}},
  language     = {{eng}},
  number       = {{5}},
  pages        = {{23--1109}},
  publisher    = {{The American Society for Clinical Investigation}},
  series       = {{Journal of Clinical Investigation}},
  title        = {{Targeting autophagy potentiates tyrosine kinase inhibitor-induced cell death in Philadelphia chromosome-positive cells, including primary CML stem cells}},
  url          = {{http://dx.doi.org/10.1172/JCI35660}},
  doi          = {{10.1172/JCI35660}},
  volume       = {{119}},
  year         = {{2009}},
}