High IGSF4 expression in pediatric M5 acute myeloid leukemia with t(9;11)(p22;q23).
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.
Pediatric Oncology/Hematology, Erasmus MC/Sophia Children's Hospital, Rotterdam, The Netherlands.
Jenny E
JE
Kuipers
Eva A
EA
Coenen
Brian V
BV
Balgobind
Jan
J
Stary
Andre
A
Baruchel
Valerie
V
de Haas
Eveline S J M
ES
de Bont
Dirk
D
Reinhardt
Gertjan J L
GJ
Kaspers
Jacqueline
J
Cloos
Astrid A
AA
Danen-van Oorschot
Monique L
ML
den Boer
Rolf
R
Marschalek
Claus
C
Meyer
Rob
R
Pieters
C Michel
CM
Zwaan
Marry M
MM
van den Heuvel-Eibrink
D000293:Adolescent; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D015153:Blotting, Western; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics*; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics*; D019175:DNA Methylation / Q000187:drug effects; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics* / Q000378:metabolism; D007223:Infant; D007231:Infant, Newborn; D007948:Leukemia, Monocytic, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D014178:Translocation, Genetic
C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D004791:Enzyme Inhibitors; D007136:Immunoglobulins; D000077209:Decitabine; D001374:Azacitidine