Pediatric Oncology/Hematology, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands.
Blood. 2011 Jan 20;117(3):928-35. doi: 10.1182/blood-2010-05-286138. Epub 2010 Nov 2.
Pediatric mixed-lineage leukemia (MLL)-rearranged acute monoblastic leukemia with t(9;11)(p22;q23) has a favorable outcome compared with other MLL-rearranged AML. The biologic background for this difference remains unknown. Therefore, we compared gene expression profiles (GEPs; Affymetrix HGU133 + 2.0) of 26 t(9;11)(p22;q23) patients with 42 other MLL-rearranged AML patients to identify differentially expressed genes. IGSF4, a cell-cell adhesion molecule, was found to be highly expressed in t(9;11)(p22;q23) patients, which was confirmed by real-time quantitative polymerase chain reaction and Western blot. IGSF4 expression within t(9;11)(p22;q23) patients was 4.9 times greater in French-American-British morphology classification (FAB)-M5 versus other FAB-types (P = .001). Methylation status investigation showed that high IGSF4-expressing t(9;11)(p22;q23) patients with FAB-M5 have no promoter hypermethylation, whereas all other cases do. Cell-line incubation with demethylating agent decitabine resulted in promoter demethylation and increased expression of IGSF4. Down-regulation of IGSF4 by siRNA did not affect proliferation or drug sensitivity. In a cohort of 79 MLL-rearranged AML cases, we show significant better overall survival for cases with high IGSF4 expression (5-year overall survival 0.70 vs 0.37, P = .03) In conclusion, we identified IGSF4 overexpression to be discriminative for t(9;11)(p22;q23) patients with FAB-M5, regulated partially by promoter methylation and resulting in survival benefit.
儿童混合谱系白血病（MLL）-易位急性单核细胞白血病伴 t（9；11）（p22；q23）与其他 MLL 重排的 AML 相比，预后较好。这种差异的生物学背景尚不清楚。因此，我们比较了 26 例 t（9；11）（p22；q23）患者和 42 例其他 MLL 重排的 AML 患者的基因表达谱（Affymetrix HGU133 + 2.0），以鉴定差异表达的基因。细胞间黏附分子 IGSF4 在 t（9；11）（p22；q23）患者中高度表达，实时定量聚合酶链反应和 Western blot 证实了这一点。在法国-美国-英国形态学分类（FAB）-M5 中，IGSF4 在 t（9；11）（p22；q23）患者中的表达是其他 FAB 类型的 4.9 倍（P =.001）。高 IGSF4 表达的 t（9；11）（p22；q23）伴 FAB-M5 患者的甲基化状态研究表明，没有启动子超甲基化，而所有其他病例均有。细胞系用去甲基化剂地西他滨孵育导致启动子去甲基化和 IGSF4 表达增加。siRNA 下调 IGSF4 不影响增殖或药物敏感性。在 79 例 MLL 重排的 AML 病例中，我们发现高 IGSF4 表达的病例总生存率显著提高（5 年总生存率为 0.70 比 0.37，P =.03）。总之，我们发现 IGSF4 过表达可区分 FAB-M5 的 t（9；11）（p22；q23）患者，部分受启动子甲基化调控，从而带来生存获益。
