RESUMO
Many cases of AML are associated with mutational activation of receptor tyrosine kinases (RTKs) such as FLT3. However, RTK inhibitors have limited clinical efficacy as single agents, indicating that AML is driven by concomitant activation of different signaling molecules. We used a functional genomic approach to identify RET, encoding an RTK, as an essential gene in multiple subtypes of AML, and observed that AML cells show activation of RET signaling via ARTN/GFRA3 and NRTN/GFRA2 ligand/co-receptor complexes. Interrogation of downstream pathways identified mTORC1-mediated suppression of autophagy and subsequent stabilization of leukemogenic drivers such as mutant FLT3 as important RET effectors. Accordingly, genetic or pharmacologic RET inhibition impaired the growth of FLT3-dependent AML cell lines and was accompanied by upregulation of autophagy and FLT3 depletion. RET dependence was also evident in mouse models of AML and primary AML patient samples, and transcriptome and immunohistochemistry analyses identified elevated RET mRNA levels and co-expression of RET and FLT3 proteins in a substantial proportion of AML patients. Our results indicate that RET-mTORC1 signaling promotes AML through autophagy suppression, suggesting that targeting RET or, more broadly, depletion of leukemogenic drivers via autophagy induction provides a therapeutic opportunity in a relevant subset of AML patients.
Assuntos
Autofagia/genética , Leucemia Mieloide Aguda/genética , Proteínas Proto-Oncogênicas c-ret/genética , Animais , Linhagem Celular Tumoral , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Humanos , Imuno-Histoquímica/métodos , Alvo Mecanístico do Complexo 1 de Rapamicina/genética , Camundongos , Camundongos Endogâmicos C57BL , Mutação/genética , Proteínas do Tecido Nervoso/genética , RNA Mensageiro/genética , Transdução de Sinais/genética , Transcriptoma/genética , Tirosina Quinase 3 Semelhante a fms/genéticaRESUMO
Cytological alterations in renal tubule epithelium cells of carp Cyprinus carpio infected with the blood flagellate Trypanoplasma borreli Laveran & Mesnil, 1901 were investigated during the course of a laboratory infection of a highly susceptible carp line. With the development of the parasitaemia, a hyperplasia of the interstitial renal tissue was induced, which resulted in a tubulus necrosis. Cytological changes were already seen in tubulus epithelium cells on Day 7 post injection (PI) of the parasite. The basilar invaginations of the cells fragmented and a swelling of mitochondria was noted. With increasing parasitaemia, on Days 14 and 21 PI, these changes progressed up to the loss of the basilar invagination and high amplitude swellings of mitochondria and deterioration of their internal membrane structures. Cells of the distal tubule segment reacted earlier and more rapidly than cells of the proximal tubule. The cytological alterations suggested a loss of function of the epithelum cells, which most likely resulted in impaired ionic and osmotic regulation of T. borreli-infected fishes. Our findings indicate that in response to the proliferation of the interstitial renal tissue cell structures of the renal tubule cells are altered quickly and in a progressive manner.