Fanconi anemia (FA) is a rare autosomal recessive disorder characterized by congenital and developmental abnormalities, hypersensitivity to DNA cross-linking agents such as mitomycin C (MMC), and strong predisposition to acute myeloid leukemia (AML). In this article, we describe clinical and molecular findings in a boy with a severe FA phenotype who developed AML by the age of 2. Although he lacked a strong family history of cancer, he was subsequently shown to carry biallelic mutations in the FANCD1/BRCA2 gene. These included an IVS7 splice-site mutation, which is strongly associated with early AML in homozygous or compound heterozygous carrier status in FA-D1 patients. Myeloid leukemia cells from this patient have been maintained in culture for more than 1 year and have been designated as the SB1690CB cell line. Growth of SB1690CB is dependent on granulocyte macrophage colony stimulating factor or interleukin-3. This cell line has retained its MMC sensitivity and has undergone further spontaneous changes in the spectrum of cytogenetic aberrations compared with the primary leukemia. This is the second AML cell line derived from an FA-D1 patient and the first proof that malignant clones arising in FA patients can retain inherited MMC sensitivity. As FA-derived malignancies are normally not very responsive to treatment, this implies there are important mechanisms of acquiring correction of the cellular FA phenotype that would explain the poor chemoresponsiveness observed in FA-associated malignancies and might also play a role in the initiation and progression of cancer in the general population.
Fanconi anemia (FA) is an inherited disease with congenital abnormalities and an extreme risk of acute myeloid leukemia (AML). Genetic events occurring during malignant transformation in FA and the biology of FA-associated AML are poorly understood, but are often preceded by the development of chromosomal aberrations involving 3q26-29 in bone marrow of FA patients. We report here the molecular cytogenetic characterization of FA-derived AML cell lines SB1685CB and SB1690CB by conventional and array comparative genomic hybridization, fluorescence in situ hybridization, and SKY. We identified gains of a 3.7 MB chromosomal region on 3q26.2-26.31, which preceded transformation to overt leukemia. This region harbors the oncogenic transcription factor EVI1. A third FA-derived cell line, FA-AML1, carried a translocation with ectopic localization of 3q26 including EVI1. Rearrangements of 3q, which are rare in childhood AML, commonly result in overexpression of EVI1, which determines specific gene expression patterns and confers poor prognosis. We detected overexpression of EVI1 in all three FA-derived AML. Our results suggest a link between the FA defect, chromosomal aberrations involving 3q and overexpression of EVI1. We hypothesize that constitutional or acquired FA defects might be a common factor for the development of 3q abnormalities in AML. In addition, cryptic imbalances as detected here might account for overexpression of EVI1 in AML without overt 3q26 rearrangements.
Transplacental transfer of taurine, a -amino acid essential for fetal and neonatal development, constitutes the primary source of taurine for the fetus. Placental transport of taurine is compromised in pregnancies complicated by intrauterine growth restriction, resulting in a reduced concentration of taurine in cord plasma. This could impact on fetal cellular metabolism as taurine represents the most abundant intracellular amino acid in many fetal cell types. In the present study, we have used pure isolates of fetal platelets and T lymphocytes from cord blood of placentas, from normal, term pregnancies, as fetal cell types to examine the cellular uptake mechanisms for taurine by the system  transporter and have compared gene and protein expression for the taurine transporter protein (TAUT) in these two cell types. System  activity in fetal platelets was 15-fold higher compared with fetal T lymphocytes (P Ͻ 0.005), mirroring greater TAUT mRNA expression in platelets than T lymphocytes (P Ͻ 0.005). Cell-specific differences in TAUT protein moieties were detected with a doublet of 75 and 80 kDa in fetal platelets compared with 114 and 120 kDa in fetal T lymphocytes, with relatively higher expression in platelets. We conclude that greater system  activity in fetal platelets compared with T lymphocytes is the result of relatively greater TAUT mRNA and protein expression. This study represents the first characterization of amino acid transporters in fetal T lymphocytes. cord blood cells; amino acid; taurine transporter protein; system  TAURINE (2-aminoethanesulfonic acid) is the most abundant free amino acid in several tissues, including the placenta and the cellular components of blood (9,21,38,41,46). It is a -amino acid with the sulfonic acid group attached to the -carbon atom and is not incorporated into proteins (14). The physiological functions of taurine are diverse, including bile and xenobiotic conjugation, regulation of neuronal excitability, membrane protection, antioxidation, detoxification, and osmoregulation (22,24,31). The nutritional requirements for taurine are met both by dietary sources and biosynthesis from cysteine and methionine (53). However, in the human fetus and the neonate, taurine is an essential amino acid, as biosynthetic capacity is almost negligible (51) due to the lack of cysteine sulfonic acid decarboxylase, which catalyses the rate-limiting step in taurine synthesis (4). Transplacental transfer of taurine from maternal blood therefore constitutes the primary source of fetal taurine.Taurine is transported across cell membranes, including those of the syncytiotrophoblast, the transporting epithelium of human placenta, by the system -amino acid transport system which is specific for taurine and other -amino acids such as -alanine and hypotaurine (29,32,36). System  is a highaffinity, low-capacity transport system that is Na ϩ -and Cl Ϫ -dependent (10) with a 2:1:1 Na ϩ :Cl Ϫ :taurine stoichiometry (39, 48). System  activity has been demonstrated in many cell types and its ca...
We previously reported that susceptibility to childhood B cell precursor ALL (BCP ALL) is associated with HLA-DPB1 alleles having glutamic acid (E) rather than lysine (K) in the P4 antigenic peptide-binding pocket. Clustering approximately 90% of DPB1 alleles into DPB69E (DP2, 6, 8) and DPB69K (DP1, 3, 4) supertypes revealed that DP2 and DP8 are associated with BCP ALL, but DP6 is also associated with non-BCP leukaemia. Here, we report that only one of seven alleles with the DP6 supertype (DPB1(*)0601) is associated with childhood leukaemia (leukaemia vs controls: odds ratio, 95% confidence interval [OR, CI]: 4.6, 2.0-10.4; corrected P=0.019), but not with childhood solid tumours or lymphomas. DPB1(*)0601 is also significantly associated with leukaemia subtypes, including BCP ALL, Pro-B ALL, T-ALL and AML. DPB1(*)0601 is significantly over-transmitted (76.9%) from parents to children with BCP ALL (OR; CI: 4.7; 1.01-22.2). Sequencing the coding region of DPB1(*)0601 revealed an exon 1-4 haplotype [T-DEAV-KIL-RVI] shared with DPB1(*)0301 and 0901, but no evidence of germline mutations in childhood leukaemia. These results suggest that the DPbeta0601 molecule may be functionally involved in childhood leukaemia. Analysis of peptide binding and T-cell activation by DPbeta0601-peptide complexes should help determine its role in childhood leukaemia causation.
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