Target Screening And Precision Therapy In T-ALL

BackgroundT-cell acute lymphoid leukemia(T-ALL)is a type of malignancy derived from T hematopoietic cells at different stages of cell differentiation.Its disease progresses rapidly,the cure rate of traditional treatment is low,and it is easy to relapse of drug resistance,which seriously endangers people’s health and life safety.Therefore,screening new specific targets,in-depth exploration of the key mechanism of T-ALL resistance,and screening effective targeted therapeutic drugs are the keys to improving the therapeutic effect of T-ALL.MethodsRNA-seq analysis,flow cytometry,and mouse tumor models were performed to identify that the FGFR1 was a potential target in T-ALL.RNA-seq,ATAC-seq,targeted metabolomics analysis,surface sensing of translation(SUn SET)assay,western blot assays,and q RT-PCR were used to investigate the underlying mechanisms of FGFR1-targeting resistance.Drug screening was conducted to identify a drug combination strategy for overcoming this drug resistance.ResultsWe identified that FGFR1 was observably upregulated in T-ALL and inversely correlated with the prognosis of patients.Functional studies showed that the knockdown of FGFR1 suppressed T-ALL cell growth and progression both in vitro and in vivo.Whereas the human T-ALL cells were resistant to FGFR1 inhibitors.Mechanistically,we identified that ATF4 was markedly upregulated.T-ALL cells became more sensitive to FGFR1 inhibitors after blocking ATF4 both in vitro and in vivo,which suggested that ATF4 was a major initiator for T-ALL resistance to FGFR1 inhibitors.Expression of ATF4 was induced by FGFR1 inhibitors through two aspects,one was enhancing chromatin accessibility in the promotor of ATF4,another was activating translation via the GCN2-e IF2α pathway.Then,ATF4 remodeled the amino acid metabolism by stimulating the expression of multiple metabolic genes and increasing the level of amino acids in cells by enhancing the synthesis of non-essential amino acids combined with the uptake of essential amino acids.In order to explore resistance solutions from the therapeutic level,we used an FDA-approved drug library for combination drug screening and found that the combination of m TOR inhibitors can overcome the resistance to FGFR1 inhibitors in TALL.In addition,we found that intracellular amino acid metabolism reprogramming can enhance the activity of m TORC1,which is an important factor for the resistance to FGFR1 inhibitors.ConclusionThese findings revealed that FGFR1 was a potential therapeutic target in T-ALL,whereas ATF4-induced amino acid metabolism reprogramming mediated the FGFR1-targeted resistance.Synergistically inhibiting FGFR1 and m TOR could overcome this obstacle,which provided a new strategy for T-ALL precision therapy.