High IGSF4 expression in pediatric M5 acute myeloid leukemia with t(9;11)(p22;q23)

• Published in: Blood Vol. 117; no. 3; pp. 928 - 935
• Main Authors: Kuipers, Jenny E., Coenen, Eva A., Balgobind, Brian V., Stary, Jan, Baruchel, Andre, de Haas, Valerie, de Bont, Eveline S.J.M., Reinhardt, Dirk, Kaspers, Gertjan J.L., Cloos, Jacqueline, Danen-van Oorschot, Astrid A., den Boer, Monique L., Marschalek, Rolf, Meyer, Claus, Pieters, Rob, Zwaan, C. Michel, van den Heuvel-Eibrink, Marry M.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 20-01-2011; Americain Society of Hematology
• Subjects: Adolescent; Azacitidine - analogs & derivatives; Azacitidine - pharmacology; Biological and medical sciences; Blotting, Western; Cell Adhesion Molecule-1; Cell Adhesion Molecules - genetics; Cell Adhesion Molecules - metabolism; Cell Line, Tumor; Child; Child, Preschool; Chromosomes, Human, Pair 11 - genetics; Chromosomes, Human, Pair 9 - genetics; Decitabine; DNA Methylation - drug effects; Enzyme Inhibitors - pharmacology; Female; Gene Expression Profiling; Gene Expression Regulation, Leukemic - drug effects; Hematologic and hematopoietic diseases; HL-60 Cells; Humans; Immunoglobulins - genetics; Immunoglobulins - metabolism; Infant; Infant, Newborn; Leukemia, Monocytic, Acute - genetics; Leukemia, Monocytic, Acute - metabolism; Leukemia, Monocytic, Acute - pathology; Male; Medical sciences; Oligonucleotide Array Sequence Analysis; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Survival Analysis; Translocation, Genetic; Human; Pediatrics; M5 acute myelocytic leukemia; Hematology; Child
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2010-05-286138

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.