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Blood, Vol. 92 No. 3 (August 1), 1998:
pp. 810-821
Clinical Significance of MLL-AF4 Fusion Transcript Expression
in the Absence of a Cytogenetically Detectable t(4;11)(q21;q23)
Chromosomal Translocation
Fatih M. Uckun,
Kim Herman-Hatten,
Mya-Lisa Crotty,
Martha G. Sensel,
Harland N. Sather,
Lisa Tuel-Ahlgren,
Mireille B. Sarquis,
Bruce Bostrom,
James B. Nachman,
Peter G. Steinherz,
Paul
S. Gaynon, and
Nyla Heerema
From the 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; The
Children's Cancer Group Operations Office, Arcadia, CA; the Department
of Preventive Medicine, University of Southern California School of
Medicine, Los Angeles; the Department of Medical and Molecular
Genetics, Indiana University School of Medicine, Indianapolis; the
Department of Pediatric Hematology-Oncology, Children's Health Care,
Minneapolis, MN; the Section of Pediatric Hematology-Oncology,
University of Chicago Medical Center, Chicago, IL; the Department of
Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY; and
the Department of Pediatric Hematology-Oncology, University of
Wisconsin, Madison.
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.
© 1998 by The American Society of Hematology.
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