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Distinct <i>FLT3</i> Pathways Gene Expression Profiles in Pediatric De Novo Acute Lymphoblastic and Myeloid Leukemia with <i>FLT3</i> Mutations: Implications for Targeted Therapy
oleh: Lizhen Zhao, Hongbo Chen, Fengli Lan, Jinjin Hao, Wenzhi Zhang, Ying Li, Yuhong Yin, Minchun Huang, Xiaoyan Wu
Format: | Article |
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Diterbitkan: | MDPI AG 2024-09-01 |
Deskripsi
Activating <i>FLT3</i> mutations plays a crucial role in leukemogenesis, but identifying the optimal candidates for <i>FLT3</i> inhibitor therapy remains controversial. This study aims to explore the impacts of <i>FLT3</i> 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 <i>FLT3</i> inhibitors. We retrospectively analyzed 243 ALL and 62 AML cases, grouping them into <i>FLT3</i>-mutant and wild-type categories, respectively. We then assessed the associations between <i>FLT3</i> mutations and the clinical manifestations, genetic characteristics, and prognosis in ALL and AML. Additionally, we compared the distinct features of <i>FLT3</i> mutations between ALL and AML. In ALL patients, those with <i>FLT3</i> mutations predominantly exhibited hyperdiploidy (48.6% vs. 14.9%, <i>p</i> < 0.001) and higher <i>FLT3</i> expression (108.02 [85.11, 142.06] FPKM vs. 23.11 [9.16, 59.14] FPKM, <i>p</i> < 0.001), but lower expression of signaling pathway-related genes such as <i>HRAS</i>, <i>PIK3R3</i>, <i>BAD</i>, <i>MAP2K2</i>, <i>MAPK3</i>, and <i>STAT5A</i> compared to <i>FLT3</i> wild-type patients. There was no significant difference in prognosis between the two groups. In contrast, AML patients with <i>FLT3</i> mutations were primarily associated with leucocytosis (82.90 [47.05, 189.76] G/L vs. 20.36 [8.90, 55.39] G/L, <i>p</i> = 0.001), <i>NUP98</i> rearrangements (30% vs. 4.8%, <i>p</i> = 0.018), elevated <i>FLT3</i> expression (74.77 [54.31, 109.46] FPKM vs. 34.56 [20.98, 48.28] FPKM, <i>p</i> < 0.001), and upregulated signaling pathway genes including <i>PIK3CB</i>, <i>AKT1</i>, <i>MTOR</i>, <i>BRAF</i>, and <i>MAPK1</i> relative to <i>FLT3</i> wild-type, correlating with poor prognosis. Notably, internal tandem duplications were the predominant type of <i>FLT3</i> mutation in AML (66.7%) with higher inserted base counts, whereas they were almost absent in ALL (6.3%, <i>p</i> < 0.001). In summary, our study demonstrated that the forms and impacts of <i>FLT3</i> mutations in ALL differed significantly from those in AML. The gene expression profiles of <i>FLT3</i>-related pathways may provide a rationale for using <i>FLT3</i> inhibitors in AML rather than ALL when <i>FLT3</i> mutations are present.