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 cellcell 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 FABM5, regulated partially by promoter methylation and resulting in survival benefit.

Additional Metadata
Keywords 5 aza 2' deoxycytidine, Western blotting, acute granulocytic leukemia, acute monocytic leukemia, adolescent, adult, article, cell adhesion molecule, controlled study, female, gene expression profiling, human, infant, major clinical study, male, methylation, newborn, overall survival, priority journal, protein IGSF4, real time polymerase chain reaction, small interfering RNA, unclassified drug
Persistent URL dx.doi.org/10.1182/blood-2010-05-286138, hdl.handle.net/1765/23597
Citation
Kuipers, J.E., Coenen, E.A., Balgobind, B.V., Stary, J., Baruchel, A., de Haas, V., … van den Heuvel-Eibrink, M.M.. (2011). High IGSF4 expression in pediatric M5 acute myeloid leukemia with t(9;11)(p22;q23). Blood, 117(3), 928–935. doi:10.1182/blood-2010-05-286138