Session: 618. Acute Lymphoblastic Leukemia: Biology, Cytogenetics, and Molecular Markers in Diagnosis and Prognosis: Poster II
Hematology Disease Topics & Pathways:
ALL, Diseases, Leukemia, apoptosis, Biological Processes, Lymphoid Malignancies, signal transduction
Using IL-7-responsive T-ALL cell lines and patient-derived xenograft (PDX) samples, we show that, in optimal culture conditions, IL-7 leads to a decrease in LC3-I/-II conversion and a reduction in both LC3 puncta and autophagosome/autolysosome formation, as determined by immunoblot, confocal microscopy, flow cytometry and electron microscopy – indicating that IL-7 inhibits autophagy in T-ALL. Using signaling-specific small molecule inhibitors (UO126 for MEK/Erk; LY294002 and rapamycin for PI3K/Akt/mTOR) we found that IL-7-mediated regulation of autophagy occurs in a complex manner that involves concomitant triggering of both pro- (via MEK/Erk) and anti- (via PI3K/Akt/mTOR) autophagic signaling, with the effects of the latter prevailing over the former. In this scenario, IL-7-mediated viability relies on PI3K/Akt/mTOR pathway and, as expected, autophagy inhibition (using MRT68921) does not prevent the ability of IL-7 to promote leukemia cell survival. In contrast, under serum starvation IL-7 promotes autophagy, and IL-7-mediated leukemia cell viability partially relies on autophagy activation, and strictly requires MEK/Erk activation. Mechanistically, we provide evidence that depending on the culture conditions, IL-7 can balance the relative activation of PI3K/Akt/mTOR and MEK/Erk pathways, inhibiting or facilitating autophagy, in order to consistently promote T-ALL cell viability. We further extended our studies to a therapy-related scenario and found that under ASNase treatment, IL-7 still promotes increased survival of leukemic cells, a possible mechanism of treatment resistance. Functionally, we demonstrate that the IL-7-mediated increase in survival under ASNase treatment is, in part, mediated via activation of autophagy, suggesting that combining ASNase administration with autophagy inhibitors may be an attractive strategy to prevent resistance.
In summary, our results indicate that IL-7 makes use of a ‘flexible strategy’ to promote T-ALL cell viability by activating both pro- and anti-autophagic pathways, which are differentially recruited, depending on the microenvironmental conditions, to prevent tumor cell death. Moreover, our findings strengthen the notion that combination therapies against PI3K/Akt/mTOR and MEK/Erk pathways may constitute a valid therapeutic avenue and highlight the potential of using autophagy inhibitors to prevent microenvironment-induced chemotherapy resistance in T-ALL.
Disclosures: Barata: Instituto de Medicina Molecular João Lobo Antunes: Patents & Royalties: Patents.
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