TY - JOUR
T1 - High IGSF4 expression in pediatric M5 acute myeloid leukemia with t(9;11)(p22;q23)
AU - Kuipers, Jenny E
AU - Coenen, Eva A
AU - Balgobind, Brian V
AU - Stary, Jan
AU - Baruchel, Andre
AU - de Haas, Valerie
AU - de Bont, Eveline S J M
AU - Reinhardt, Dirk
AU - Kaspers, Gertjan J L
AU - Cloos, Jacqueline
AU - Danen-van Oorschot, Astrid A
AU - den Boer, Monique L
AU - Marschalek, Rolf
AU - Meyer, Claus
AU - Pieters, Rob
AU - Zwaan, C Michel
AU - van den Heuvel-Eibrink, Marry M
PY - 2011/1/20
Y1 - 2011/1/20
N2 - 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.
AB - 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.
KW - Adolescent
KW - Azacitidine/analogs & derivatives
KW - Blotting, Western
KW - Cell Adhesion Molecule-1
KW - Cell Adhesion Molecules/genetics
KW - Cell Line, Tumor
KW - Child
KW - Child, Preschool
KW - Chromosomes, Human, Pair 11/genetics
KW - Chromosomes, Human, Pair 9/genetics
KW - DNA Methylation/drug effects
KW - Decitabine
KW - Enzyme Inhibitors/pharmacology
KW - Female
KW - Gene Expression Profiling
KW - Gene Expression Regulation, Leukemic/drug effects
KW - HL-60 Cells
KW - Humans
KW - Immunoglobulins/genetics
KW - Infant
KW - Infant, Newborn
KW - Leukemia, Monocytic, Acute/genetics
KW - Male
KW - Oligonucleotide Array Sequence Analysis
KW - RNA Interference
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - Survival Analysis
KW - Translocation, Genetic
U2 - 10.1182/blood-2010-05-286138
DO - 10.1182/blood-2010-05-286138
M3 - Article
C2 - 21045196
SN - 0006-4971
VL - 117
SP - 928
EP - 935
JO - Blood
JF - Blood
IS - 3
ER -