Lifelong persistence of AML associated MLL partial tandem duplications (MLL-PTD) in healthy adults

Department of Hematology and Oncology, University of Goettingen, Goettingen, Germany.
Leukemia Research (Impact Factor: 2.35). 10/2006; 30(9):1091-6. DOI: 10.1016/j.leukres.2006.02.005
Source: PubMed


AML-associated MLL-PTD contribute to leukemogenesis by a gain of function and confer an unfavorable prognosis. Like other leukemia associated aberrations they are also present in healthy adults. To delineate the leukemogenic mechanism we tracked down MLL-PTD in normal hematopoiesis and investigated cord blood samples. MLL-PTD were observed in 56/60 (93%) of all cord bloods. In contrast to AML, the transcript frequency in cord blood was four log scales lower as determined by real-time PCR. The CD34+ progenitor cell, CD33+ myeloid, CD19+ B-lymphoid and CD3+ T-lymphoid subfractions were positive. The ubiquitous presence of MLL-PTD in cord blood implicates a lifelong exposure, not an accumulation during lifetime. Since also present in the stem cell subfraction, these factors seem not to be major determinants in MLL-PTD leukemogenesis.

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    • "As indicated above, several studies have reported the presence of leukemia-lymphoma-associated fusion genes (e.g., BCR/ABL1, IGH/BCL2, TCRβ/γ) in normal individuals. In tandem partial duplications of MLL have been detected in almost all bone marrow and peripheral blood samples from healthy donors (Schnittger et al., 1998; Bäsecke et al., 2002, 2006), but there is only one report of translocations involving MLL in normal individuals. Uckum et al. (1998) used nested PCR to show that rearrangements involving MLL and the transcription factor AF4, resulted in the translocation t(4;11)(q21;q23) in bone marrow samples from fetuses and normal children, as well as in fetal liver samples. "
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    ABSTRACT: Chromosomal translocations are characteristic of hematopoietic neoplasias and can lead to unregulated oncogene expression or the fusion of genes to yield novel functions. In recent years, different lymphoma/leukemia-associated rearrangements have been detected in healthy individuals. In this study, we used inverse PCR to screen peripheral lymphocytes from 100 healthy individuals for the presence of MLL (Mixed Lineage Leukemia) translocations. Forty-nine percent of the probands showed MLL rearrangements. Sequence analysis showed that these rearrangements were specific for MLL translocations that corresponded to t(4;11)(q21;q23) (66%) and t(9;11) (20%). However, RT-PCR failed to detect any expression of t(4;11)(q21;q23) in our population. We suggest that 11q23 rearrangements in peripheral lymphocytes from normal individuals may result from exposure to endogenous or exogenous DNA-damaging agents. In practical terms, the high susceptibility of the MLL gene to chemically-induced damage suggests that monitoring the aberrations associated with this gene in peripheral lymphocytes may be a sensitive assay for assessing genomic instability in individuals exposed to genotoxic stress.
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    • "Interestingly, it has been postulated that tumor-associated translocations in peripheral lymphocytes could be transitory, since consecutive blood samples are not always positive for gene fusions as demonstrated for the BCR/ABL hybrid gene (Biernaux et al., 1995) and for other rearrangements in treated patients (Bäsecke et al., 2006). Other authors suggested that such rearrangements could be expressed in hematopoietic cells that have entered the apoptotic pathway and that might have already lost their significance (Bose et al., 1998), being irrelevant in mature cells. "
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