Uckun F M, Herman-Hatten K, Crotty M L, Sensel M G, Sather H N, Tuel-Ahlgren L, Sarquis M B, Bostrom B, Nachman J B, Steinherz P G, Gaynon P S, Heerema N
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.
Blood. 1998 Aug 1;92(3):810-21.
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.
对17名婴儿和127名新诊断为急性淋巴细胞白血病（ALL）的儿童的骨髓（BM）白血病细胞，以及胎儿肝脏、骨髓和正常婴儿骨髓样本，使用标准细胞遗传学技术分析t(4;11)易位的存在情况，并使用标准逆转录聚合酶链反应（RT-PCR）检测以及比标准RT-PCR敏感100倍的巢式RT-PCR检测MLL-AF4融合转录本的表达。总体而言，通过标准和/或巢式RT-PCR检测确定，17名婴儿中有9名以及127名非婴儿儿科ALL患者中有17名MLL-AF4融合转录本表达呈阳性。所有MLL-AF4(+)病例的E2A-PBX1或BCR-ABL融合转录本表达均为阴性。尽管9名MLL-AF4(+)婴儿中有8名在细胞遗传学上可检测到t(4;11)(q21;q23)，但17名MLL-AF4(+)非婴儿中有15名t(4;11)为阴性。MLL-AF4(+) ALL婴儿的预后较差，而MLL-AF4(+)/t(4;11)-的非婴儿患者的预后与MLL-AF4(-)患者相似。值得注意的是，通过巢式RT-PCR在16份胎儿骨髓中的4份、13份胎儿肝脏中的5份以及6份正常婴儿骨髓中的1份中也检测到了MLL-AF4转录本，但在44份儿科ALL患者的缓解期骨髓标本中均未检测到。我们的结果提供了前所未有的证据，表明MLL-AF4融合转录本可存在于正常造血细胞中，这表明它们的表达不足以使正常淋巴细胞前体发生白血病转化。
