RET-mediated autophagy suppression as targetable co-dependence in acute myeloid leukemia

Area of Science:

• Oncology
• Molecular Biology
• Signal Transduction

Background:

• Acute myeloid leukemia (AML) often involves mutations in receptor tyrosine kinases (RTKs) like FLT3.
• Single-agent RTK inhibitors show limited efficacy, suggesting multiple signaling pathways are involved in AML pathogenesis.

Purpose of the Study:

• To identify novel essential genes and signaling pathways in AML.
• To investigate the role of RET receptor tyrosine kinase (RTK) signaling in AML.
• To explore therapeutic strategies targeting RET signaling in AML.

Main Methods:

• Functional genomic screening to identify essential genes in AML.
• Analysis of RET signaling activation via ligand/co-receptor complexes (ARTN/GFRA3, NRTN/GFRA2).
• Interrogation of downstream pathways, including mTORC1 and autophagy.
• In vitro studies using AML cell lines and in vivo studies using mouse models.
• Transcriptome and immunohistochemistry analyses of patient samples.

Main Results:

• RET was identified as an essential gene in multiple AML subtypes.
• AML cells exhibit activated RET signaling, promoting leukemogenesis through mTORC1-mediated autophagy suppression.
• RET inhibition led to autophagy upregulation and FLT3 depletion, impairing AML cell growth.
• Elevated RET mRNA and co-expression of RET and FLT3 proteins were observed in a significant proportion of AML patients.

Conclusions:

• RET-mTORC1 signaling is a key driver in a subset of AML by suppressing autophagy.
• Targeting RET or inducing autophagy presents a potential therapeutic avenue for AML patients with activated RET signaling.