AI Article Synopsis
- The FLT3-ITD mutation is linked to poor outcomes in acute myeloid leukemia (AML) and current treatments with FLT3 inhibitors do not effectively eliminate leukemia stem cells (LSCs).
- Inhibiting autophagy was found to negatively affect the stem cell function of FLT3-ITD AML LSCs, leading to increased mitochondrial activity, but combining autophagy inhibition with TKI treatment resulted in unexpected counterproductive effects on LSC targeting.
- The study highlights the complex relationship between autophagy and p53 activity, suggesting that understanding these mechanisms could lead to better strategies for effectively targeting both LSCs and their ability to regenerate in AML.
Article Abstract
The FLT3-ITD mutation is associated with poor prognosis in acute myeloid leukemia (AML). FLT3 tyrosine kinase inhibitors (TKIs) demonstrate clinical efficacy but fail to target leukemia stem cells (LSC) and do not generate sustained responses. Autophagy is an important cellular stress response contributing to hematopoietic stem cells (HSC) maintenance and promoting leukemia development. Here we investigated the role of autophagy in regulating FLT3-ITD AML stem cell function and response to TKI treatment. We show that autophagy inhibition reduced quiescence and depleted repopulating potential of FLT3-ITD AML LSC, associated with mitochondrial accumulation and increased oxidative phosphorylation. However, TKI treatment reduced mitochondrial respiration and unexpectedly antagonized the effects of autophagy inhibition on LSC attrition. We further show that TKI-mediated targeting of AML LSC and committed progenitors was p53-dependent, and that autophagy inhibition enhanced p53 activity and increased TKI-mediated targeting of AML progenitors, but decreased p53 activity in LSC and reduced TKI-mediated LSC inhibition. These results provide new insights into the role of autophagy in differentially regulating AML stem and progenitor cells, reveal unexpected antagonistic effects of combined oncogenic tyrosine kinase inhibition and autophagy inhibition in AML LSC, and suggest an alternative approach to target AML LSC quiescence and regenerative potential.
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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9617791 | PMC |
| http://dx.doi.org/10.1038/s41375-022-01719-6 | DOI Listing |
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