Clinical significance of MLL-AF4 fusion transcript expression in the absence of a cytogenetically detectable t(4;11)(q21;q23) chromosomal translocation.
Leukemic cells from bone marrow (BM) of 17 infants and 127 children with newly diagnosed ALL, as well as fetal liver and BM and normal infant BM samples, were analyzed for presence of a t(4;11) translocation using standard cytogenetic techniques and expression of an MLL-AF4 fusion transcript using standard reverse transcriptase-polymerase chain reaction (RT-PCR) assays as well as nested RT-PCR that is 100-fold more sensitive than standard RT-PCR. Overall, 9 of 17 infants and 17 of 127 noninfant pediatric ALL patients were positive for expression of MLL-AF4 fusion transcripts, as determined by standard and/or nested RT-PCR assays. None of the MLL-AF4(+) cases were positive for E2A-PBX1 or BCR-ABL fusion transcript expression. Although 8 of 9 MLL-AF4(+) infants had cytogenetically detectable t(4;11)(q21;q23), 15 of the 17 MLL-AF4(+) noninfants were t(4;11)-. Infants with MLL-AF4(+) ALL had poor outcomes, whereas non-infant MLL-AF4(+)/t(4;11)- patients had favorable outcomes similar to MLL-AF4(-) patients. Notably, MLL-AF4 transcripts also were detected by nested RT-PCR in 4 of 16 fetal BMs, 5 of 13 fetal livers, and 1 of 6 normal infant BMs, but not in any of the 44 remission BM specimens from pediatric ALL patients. Our results provide unprecedented evidence that MLL-AF4 fusion transcripts can be present in normal hematopoietic cells, indicating that their expression is insufficient for leukemic transformation of normal lymphocyte precursors.
Uckun
F M
FM
Children's Cancer Group ALL Biology Reference Laboratory, Parker Hughes Cancer Center, and the Departments of Biology, Immunology, and Molecular Genetics, Hughes Institute, St Paul, MN, USA.
Herman-Hatten
K
K
Crotty
M L
ML
Sensel
M G
MG
Sather
H N
HN
Tuel-Ahlgren
L
L
Sarquis
M B
MB
Bostrom
B
B
Nachman
J B
JB
Steinherz
P G
PG
Gaynon
P S
PS
Heerema
N
N
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics; D001853:Bone Marrow / Q000473:pathology; D016026:Bone Marrow Transplantation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D002880:Chromosomes, Human, Pair 11 / Q000235:genetics* / Q000648:ultrastructure; D002894:Chromosomes, Human, Pair 4 / Q000235:genetics* / Q000648:ultrastructure; D003131:Combined Modality Therapy; D018572:Disease-Free Survival; D005260:Female; D005326:Fetal Proteins / Q000032:analysis; D018507:Gene Expression Regulation, Developmental; D015973:Gene Expression Regulation, Leukemic; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D007223:Infant; D008099:Liver / Q000196:embryology / Q000473:pathology; D008297:Male; D051788:Myeloid-Lymphoid Leukemia Protein; D009363:Neoplasm Proteins / Q000032:analysis* / Q000096:biosynthesis / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000235:genetics*; D016133:Polymerase Chain Reaction / Q000379:methods; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D011379:Prognosis; D012074:Remission Induction; D012680:Sensitivity and Specificity; D016019:Survival Analysis; D014178:Translocation, Genetic / Q000235:genetics*; D016896:Treatment Outcome
D014408:Biomarkers, Tumor; D005326:Fetal Proteins; C113855:MLL-AF4 fusion protein, human; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D051788:Myeloid-Lymphoid Leukemia Protein