Abstract
FLT3-mutant acute myeloid leukemia (AML) is an aggressive form of leukemia with poor prognosis. Treatment with FLT3 inhibitors frequently produces a clinical response, but the disease nevertheless often recurs. Recent studies have revealed system-wide gene expression changes in FLT3-mutant AML cell lines in response to drug treatment. Here we sought a systems-level understanding of how these cells mediate these drug-induced changes. Using RNAseq data from AML cells with an internal tandem duplication FLT3 mutation (FLT3-ITD) under six drug treatment conditions including quizartinib and dexamethasone, we identified seven distinct gene programs representing diverse biological processes involved in AML drug-induced changes. Based on the literature knowledge about genes from these modules, along with public gene regulatory network databases, we constructed a network of FLT3-ITD AML. Applying the BooleaBayes algorithm to this network and the RNAseq data, we created a probabilistic, data-driven dynamical model of acquired resistance to these drugs. Analysis of this model reveals several interventions that may disrupt targeted parts of the system-wide drug response. We anticipate co-targeting these points may result in synergistic treatments that can overcome resistance and prevent eventual recurrence.
Highlights
Acute myeloid leukemia (AML), characterized by the pathological accumulation of myeloblast cells in blood or bone marrow, is a heterogeneous and aggressive form of leukemia
Targeting the therapeutic vulnerabilities of drug-tolerant FLT3 mutant AML cells can enhance the anti-leukemic efficacy of FLT3 inhibitors to eliminate minimal residual disease, mutational drug resistance and relapse
Quiz + Dex), (5) Quiz + Dex for five days, and (6)
Summary
Acute myeloid leukemia (AML), characterized by the pathological accumulation of myeloblast cells in blood or bone marrow, is a heterogeneous and aggressive form of leukemia. Targeting the therapeutic vulnerabilities of drug-tolerant FLT3 mutant AML cells can enhance the anti-leukemic efficacy of FLT3 inhibitors to eliminate minimal residual disease, mutational drug resistance and relapse. The mechanisms underlying this phenotypic change are not fully understood. A recent study found that DTPs exhibit the upregulation of inflammation pathways, and combination treatment with quizartinib (a FLT3 inhibitor) and dexamethasone (a glucocorticoid that reduces inflammation) was synergistic [4] This is an example of reprogramming therapy, in which the phenotypes or gene expression patterns induced by one drug are countered by another simultaneous intervention
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
