Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Int J Mol Sci. 2024 Sep 4;25(17):9581. doi: 10.3390/ijms25179581.
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.
激活突变在白血病发生中起着至关重要的作用，但确定抑制剂治疗的最佳候选者仍存在争议。本研究旨在探讨儿童急性淋巴细胞白血病（ALL）和急性髓系白血病（AML）中突变的影响，并比较两种类型的突变谱，以启发抑制剂的靶向应用。我们回顾性分析了 243 例 ALL 和 62 例 AML 病例，分别将其分为突变型和野生型。然后，我们评估了 ALL 和 AML 中突变与临床表现、遗传特征和预后之间的关系。此外，我们比较了 ALL 和 AML 中突变的特征差异。在 ALL 患者中，突变患者主要表现为超二倍体（48.6%比 14.9%， ＜0.001）和更高的 表达（108.02 [85.11，142.06] FPKM 比 23.11 [9.16，59.14] FPKM， ＜0.001），但信号通路相关基因的表达水平较低，如 、 、 、 、 和 。两组患者的预后无显著差异。相比之下，AML 突变患者主要与白细胞增多症相关（82.90 [47.05，189.76] G/L 比 20.36 [8.90，55.39] G/L， ＝0.001）、 重排（30%比 4.8%， ＝0.018）、更高的 表达（74.77 [54.31，109.46] FPKM 比 34.56 [20.98，48.28] FPKM， ＜0.001）以及信号通路相关基因的上调，包括 、 、 、 和 ，与预后不良相关。值得注意的是，AML 中 突变的主要类型为内部串联重复（66.7%），插入碱基数量较高，而 ALL 中几乎不存在（6.3%， ＜0.001）。综上所述，本研究表明，ALL 中 突变的形式和影响与 AML 显著不同。 相关途径的基因表达谱可能为存在 突变时 AML 而非 ALL 中使用 抑制剂提供依据。
