| 000 | 02527 am a22003733u 4500 | ||
|---|---|---|---|
| 042 | _adc | ||
| 100 | 1 | 0 |
_aIanniciello, Angela _eauthor _91022 |
| 700 | 1 | 0 |
_aZarou, Martha M. _eauthor _91023 |
| 700 | 1 | 0 |
_aRattigan, Kevin M. _eauthor _91024 |
| 700 | 1 | 0 |
_aScott, Mary _eauthor _91025 |
| 700 | 1 | 0 |
_aDawson, Amy _eauthor _91026 |
| 700 | 1 | 0 |
_aDunn, Karen _eauthor _91027 |
| 700 | 1 | 0 |
_aBrabcova, Zuzana _eauthor _91028 |
| 700 | 1 | 0 |
_aKalkman, Eric R. _eauthor _91029 |
| 700 | 1 | 0 |
_aNixon, Colin _eauthor _91030 |
| 700 | 1 | 0 |
_aMichie, Alison M. _eauthor _91031 |
| 700 | 1 | 0 |
_aCopland, Mhairi _eauthor _91032 |
| 700 | 1 | 0 |
_aVetrie, David _eauthor _91033 |
| 700 | 1 | 0 |
_aAmbler, Martin _eauthor _91034 |
| 700 | 1 | 0 |
_aSaxty, Barbara _eauthor _91035 |
| 700 | 1 | 0 |
_aHelgason, G. Vignir _eauthor _91036 |
| 245 | 0 | 0 | _aULK1 inhibition promotes oxidative stress-induced differentiation and sensitizes leukemic stem cells to targeted therapy |
| 260 | _c2021-09-29. | ||
| 500 | _a/pmc/articles/PMC7612079/ | ||
| 500 | _a/pubmed/34586834 | ||
| 520 | _aInhibition of autophagy has been proposed as a potential therapy for individuals with cancer. However, current lysosomotropic autophagy inhibitors have demonstrated limited efficacy in clinical trials. Therefore, validation of novel specific autophagy inhibitors using robust preclinical models is critical. In chronic myeloid leukemia (CML), minimal residual disease is maintained by persistent leukemic stem cells (LSCs), which drive tyrosine kinase inhibitor (TKI) resistance and patient relapse. Here, we show that deletion of autophagy-inducing kinase ULK1 (unc-51-like autophagy activating kinase 1) reduces growth of cell line and patient-derived xenografted CML cells in mouse models. Using primitive cells, isolated from individuals with CML, we demonstrate that pharmacological inhibition of ULK1 selectively targets CML LSCs ex vivo and in vivo, when combined with TKI treatment. The enhanced TKI sensitivity after ULK1-mediated autophagy inhibition is driven by increased mitochondrial respiration and loss of quiescence and points to oxidative stress-induced differentiation of CML LSCs, proposing an alternative strategy for treating patients with CML. | ||
| 540 | _a | ||
| 540 | _aexclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works | ||
| 546 | _aen | ||
| 690 | _aArticle | ||
| 655 | 7 |
_aText _2local |
|
| 786 | 0 | _nSci Transl Med | |
| 856 | 4 | 1 |
_uhttp://dx.doi.org/10.1126/scitranslmed.abd5016 _zConnect to this object online. |
| 999 |
_c1650 _d1650 |
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