Distinct Pathways Gene Expression Profiles in Pediatric De Novo Acute Lymphoblastic and Myeloid Leukemia with Mutations: Implications for Targeted Therapy.

Activating mutations plays a crucial role in leukemogenesis, but identifying the optimal candidates for inhibitor therapy remains controversial. This study aims to explore the impacts of mutations in pediatric acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) and to compare the mutation profiles between the two types to inspire the targeted application of inhibitors. We retrospectively analyzed 243 ALL and 62 AML cases, grouping them into -mutant and wild-type categories, respectively. We then assessed the associations between mutations and the clinical manifestations, genetic characteristics, and prognosis in ALL and AML. Additionally, we compared the distinct features of mutations between ALL and AML. In ALL patients, those with mutations predominantly exhibited hyperdiploidy (48.6% vs. 14.9%, < 0.001) and higher expression (108.02 [85.11, 142.06] FPKM vs. 23.11 [9.16, 59.14] FPKM, < 0.001), but lower expression of signaling pathway-related genes such as , , , , , and compared to wild-type patients. There was no significant difference in prognosis between the two groups. In contrast, AML patients with mutations were primarily associated with leucocytosis (82.90 [47.05, 189.76] G/L vs. 20.36 [8.90, 55.39] G/L, = 0.001), rearrangements (30% vs. 4.8%, = 0.018), elevated expression (74.77 [54.31, 109.46] FPKM vs. 34.56 [20.98, 48.28] FPKM, < 0.001), and upregulated signaling pathway genes including , , , , and relative to wild-type, correlating with poor prognosis. Notably, internal tandem duplications were the predominant type of mutation in AML (66.7%) with higher inserted base counts, whereas they were almost absent in ALL (6.3%, < 0.001). In summary, our study demonstrated that the forms and impacts of mutations in ALL differed significantly from those in AML. The gene expression profiles of -related pathways may provide a rationale for using inhibitors in AML rather than ALL when mutations are present.