The disease-governing lesions-tissue therapies affect the evolution of leukemia, especially acute myeloid leukemia (AML). One of them is FLT3-internal tandem duplication (FLT3-ITD) that is among the most common alterations which may affect up to 25-30 % of patients with AML and is closely linked to hyperleukocytosis, a fast course of illness and increased probability of recall. In comparison, TP53 are less frequent mutations (occurring in 5-10 % of all AML) and nevertheless are found in up to 50 % of therapy-related AML and in cases of complex karyotype, being overall a dismal prognostic feature, and median overall survival rarely better than 6 months. The study herein characterizes functions of genomic interactions between TP53 loss-of-function and FLT3-ITD activation to show how their concurrence augments in leukemogenesis. Recent cohort studies have confirmed that patients with dual mutation have significantly high white blood cell counts at diagnosis (median > 50 x 10 9/L), and are also innately resistant to FLT3 inhibitors including midostaurin and gilteritinib with response rates being less than 20 %. The in vitro experiments also demonstrate that the inactivation of TP53 increases FLT3-ITD induced STAT5 and PI3K/Akt signaling up to 150 % over its basal levels and inhibits apoptosis greater than 70 % in FLT3-ITD alone. Collectively, these results reflect the negative consequences of TP53 mutations in relation to FLT3-ITD mutations to explain the underlying mechanisms that contribute to the poor leukemic phenotypes and reduces the efficacy of targeted treatments. Recently, a report showed that patients affected by co-mutated TP53 and FLT3-ITD had 2.5 times higher levels of relapse and failure to recapture treatment as compared to mono-mutated patients, thus indicating the need of targeting two pathways simultaneously. Before urgent results are reported, preliminary findings of earlystage clinical trials of combinations of drugs that target these mutations together, including both dual FLT 3 / MCL 1 and TP 53 reactivators, such as APR 246, have reported response rates with greater than 35 % in this high risk patient group. Therefore, combined blockade of TP53 and FLT3-ITD would be a valued line of research to enhance outcome in resistant or remission AML patients..
Keywords: Acute Myeloid Leukemia, TP53 mutation, FLT3-ITD, Drug Resistance, Co-mutation Synergy.
How to cite this article: Khan UA, Nassar NT, Bekchanova MK, Eshkaraev S, Khudaykulova F, Pandiyan B, Jabeen S, Mehboob AA, Ayaz M, Genomic Synergy of TP53 and FLT3-ITD Mutations as Drivers of Aggressive Leukemia and Therapeutic Resistance..Int J Drug Deliv Technol. 2026;16 (1s): 376-382; DOI: 10.25258/ijddt.16. 376-382