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PubMed2006

Lineage dependency and lineage-survival oncogenes in human cancer.

Although cell-lineage and differentiation models dominate tumour classification and treatment, the recognition that cancer is also a genomic disease has prompted a reconfiguration of cancer taxonomies according to molecular criteria. Recent evidence indicates that a synthesis of lineage-based and genetic paradigms might offer new insights into crucial and therapeutically pliable tumour dependencies. For example, MITF (microphthalmia-associated transcription factor), which is a master regulator of the melanocyte lineage, might become a melanoma oncogene when deregulated in certain genetic contexts. MITF and other lineage-survival genes therefore implicate lineage dependency (or lineage addiction) as a newly recognized mechanism that is affected by tumour genetic alterations.

Cell Lineage↗

PubMed2002

Avian models to study the transcriptional control of hematopoietic lineage commitment and to identify lineage-specific genes.

E26 is an avian acute leukemia virus with a profound ability to transform multipotent hematopoietic progenitor cells both in vivo and in vitro. Progenitor cells transformed by this virus can be expanded in vitro as undifferentiated clones for up to two months and can also be induced to differentiate into cells of the erythroid, eosinophilic, thrombocytic, and myelomonocytic lineages with reproducible kinetics. Aside from the proliferative stimulus provided by the E26 oncoprotein, these cells are remarkably similar to normal hematopoietic progenitors. They therefore provide an ideal assay system for determining the influence of ectopically expressed transcription factors on both maturation and commitment to several hematopoietic lineages. Results from experiments using this system suggest that subtle shifts in the balance of lineage-restricted transcription factors can result in profound changes in phenotype and challenge the notion that lineage commitment is a uni-directional process. Analysis of the regulatory elements governing the expression of these genes has provided novel mechanistic insights into the transcriptional control of hematopoiesis. In addition to their utility in deciphering the control of lineage commitment, the ability to grow large numbers of undifferentiated and more mature hematopoietic cells has facilitated the discovery of a number of novel, lineage-restricted genes. Analysis of the proteins encoded by these genes is helping to clarify the role of a number of membrane proteins in the interaction between hematopoietic cells and their microenvironments.

Animals↗

PubMed1989

Antigenic phenotypes of cultured malignant astrocytomas: identification of lineage-consistent, lineage-independent and putative tumor-restricted antigenic expression.

The treatment of CNS neoplasms with monoclonal antibody-mediated immunotherapy optimally requires the identification of tumor restricted cell surface antigens. However, little is known regarding the antigenic phenotype(s) of malignant astrocytomas. The interrelated expression of four neuroectodermal tumor antigens, CNT/11, AJ8, A010 and CNT/2, has been studied in cultured malignant gliomas and correlated with anchorage independent growth, morphology, glial fibrillary acidic protein, and the surface expression of other antigens. Many of these latter antigens have been reported to be expressed by specific fetal and differentiated adult cell lineages or tissues, as well as certain classes of malignant tumors. The tumor-associated expression of these antigens may be broadly classified as lineage-consistent, lineage-independent or putatively tumor-restricted. Malignant glioma tumor antigenic heterogeneity represents the expression of neuroectodermal and non-neuroectodermal cell surface markers. The importance of this observation is 2-fold. Lineage-independent antigen expression may be an indication of altered genome regulatory processes within tumor cells, and thus reflect the degree of anaplasia. The identification of lineage-consistent and lineage-independent tumor associated antigens may contribute to the selection of "target" antigens and the prediction of toxicity for monoclonal antibody mediated immunotherapy.

Antigens, Neoplasm↗

PubMed2026

Bayesian inference of lineage trees by joint analysis of single-cell multimodal lineage-tracing data with BiLinT.

The advent of single-cell lineage-tracing technologies has enabled the simultaneous profiling of gene expression and lineage barcodes. However, accurate, high-resolution reconstruction of cell lineage trees remains challenging because most existing approaches treat these modalities separately and therefore fail to fully exploit their complementary information. Here we present BiLinT, a Bayesian framework that jointly models multimodal single-cell lineage-tracing data for lineage tree reconstruction. BiLinT integrates barcode evolution (a continuous-time Markov chain) with gene expression dynamics (an Ornstein-Uhlenbeck process) within a unified probabilistic model. Across synthetic and real data sets, BiLinT provides accurate lineage-tree reconstruction and reveals differentiation-associated clonal structure and developmental fate biases.

Journal Article↗

PubMed2002

Restriction fragment length polymorphisms detected with novel DNA probes differentiate among diverse lineages of serogroup 4 Listeria monocytogenes and identify four distinct lineages in serotype 4b.

Listeria monocytogenes of serotype 4b has been implicated in numerous outbreaks of food-borne listeriosis and in ca. 40% of sporadic cases. Strains of this serotype appear to be relatively homogeneous genetically, and molecular markers specific for distinct serotype 4b lineages have not been frequently identified. Here we show that DNA fragments derived from the putative mannitol permease locus of Listeria monocytogenes had an unexpectedly high potential to differentiate among different strains of serotype 4b when used as probes in Southern blotting of EcoRI-digested genomic DNA, yielding four distinct restriction fragment length polymorphism (RFLP) patterns. Strains of two epidemic-associated lineages, including the major epidemic clone implicated in several outbreaks in Europe and North America, had distinct RFLPs which differed from those of all other serotype 4b strains that we screened but which were encountered among strains of serotypes 1/2b and 3b. In addition, three serogroup 4 lineages were found to have unique RFLPs that were not encountered among any other L. monocytogenes strains. One was an unusual lineage of serotype 4b, and the other two were members of the serotype 4a and 4c group. The observed polymorphisms may reflect evolutionary relationships among lineages of L. monocytogenes and may facilitate detection and population genetic analysis of specific lineages.

Bacterial Typing Techniques↗

PubMed2006

A new fluorogenic real-time RT-PCR assay for detection of lineage 1 and lineage 2 West Nile viruses.

West Nile virus represents an emerging threat for animal and human health worldwide. This virus exhibits a marked genetic variation, with at least 2 distinct evolutionary lineages. Lineage 1 has been recognized in Africa, Asia, Europe, Oceania, and more recently in the Americas, whereas lineage 2 is restricted to Africa. Perhaps for this reason, the available real-time RT-PCR methods for detecting West Nile virus genome have mainly focused on lineage 1. However, both viruses may potentially be spread beyond their endemic areas by migratory birds. This report describes a new real-time reverse transcription-PCR (RT-PCR) method based on a 5'-Taq nuclease-3' minor groove binder DNA probe (TaqMan MGB) that allows the detection of a wide range of West Nile virus isolates, including both lineages 1 and 2. This method was able to detect West Nile viruses from different origins (North and Central Africa, Middle East, Europe, and North America), whereas other flaviviruses (Usutu, Dengue, Yellow fever) analyzed in parallel remained negative. The sensitivity achieved by this assay was 10(-2)-10(-3) pfu/tube. This method, which can be performed in 96-well format, could be suitable for the large-scale surveillance of West Nile virus in areas where both lineages can potentially spread.

Animals↗

PubMed1985

Cell-lineage antigens of the stem cell-megakaryocyte-platelet lineage are associated with the platelet IIb-IIIa glycoprotein complex.

The stem cell-platelet lineage is uniquely defined by platelet cell-lineage antigens. These antigens are present on all stem cells measured by the spleen colony assay and become restricted to the platelet cell lineage as differentiation proceeds. In this study, anti-platelet serum (APS) has been used to identify cells in the bone marrow that express platelet cell-lineage antigens and to identify platelet cell surface molecules expressing these antigens. Anti-platelet IgG extensively absorbed with brain, thymus, and peritoneal cells bound selectively to stem cells, megakaryocyte progenitor cells (Mk-CFC), and megakaryocytes in CBA mouse bone marrow and to blood platelets. No other hemopoietic cell type, tissue, cell line, or tumor cell bound significant amounts of antibody against platelet cell-lineage antigens as determined by ability to absorb the anti-stem cell activity in APS. Studies with lactoperoxidase-labeled platelets showed that two major iodinated proteins of Mr = 114,000 and 138,000 were immunoprecipitated with APS and with antiserum that had been extensively absorbed. These proteins correspond to the platelet IIb-IIIa glycoprotein complex, which is known to express receptors for collagen and fibrinogen, molecules known to influence hemopoietic cell proliferation and tumor cell growth. A panel of six monoclonal antibodies against human IIb-IIIa inhibited spleen colony formation by 17% to 100%, J15 and A5.15 also being cytotoxic for granulocyte-macrophage progenitor cells and Mk-CFC. Other platelet monoclonal antibodies did not inhibit spleen colony formation. Although APS inhibited fibrinogen binding to platelets and platelet aggregation, these activities were greatly reduced with absorbed antiserum. Furthermore, fibrinogen treatment of bone marrow did not block the anti-stem cell activity in APS. Thus the evidence is consistent with expression of platelet cell-lineage antigens on the platelet IIb-IIIa glycoprotein complex at a site removed from the fibrinogen binding site.

Animals↗

PubMed1994

Expression of lineage restricted transcription factors precedes lineage specific differentiation in a multipotent haemopoietic progenitor cell line.

Lineage commitment and differentiation are likely to be coordinated by the combined effects of multiple transcription factors acting on numerous different target genes. The mechanisms by which lineage-restricted patterns of transcription factor expression are established are therefore of particular relevance to our understanding of the role of transcription factors both in normal development and in oncogenesis. Here, we report that the genes for the lineage-restricted transcription factors SCL, GATA-1 and GATA-2 are expressed in all multipotent, IL-3-dependent, haemopoietic progenitor cell lines tested. Moreover, a liquid differentiation assay has been used to demonstrate down regulation of SCL, GATA-1, GATA-2 and PU-1 during differentiation into non-expressing lineages. These data support the concept that multiple lineage-restricted transcription factors are expressed prior to lineage commitment.

Cell Line↗

PubMed1998

Molecular requirements for lineage commitment in the thymus--antibody-mediated receptor engagements reveal a central role for lck in lineage decisions.

Recent experiments in our laboratory have focused on the receptor engagements required for the differentiation of fully mature, single positive thymocytes from their double positive precursors. We have used a novel approach which involves the ligation of surface receptors on immature thymocytes with genetically engineered F(ab1)2 reagents, which, unlike conventional antibodies, do not aggregate the CD3 complex to such an extent as to induce extensive deletion of these cells. The experimental data presented in this review indicate that differentiation of the two mature CD4 and CD8 lineages occurs in response to distinct intracellular signals induced by particular receptor engagements. The data suggest that the tyrosine kinase p56lck (lck) plays a crucial role in determining lineage choice, in that maturation of thymocytes into the CD4 lineage occurs upon recruitment of active lck to the T-cell receptor (TCR)/CD3 complex, whereas CD8 maturation can be induced by CD3 ligation in the absence of co-receptor-mediated lck recruitment. A central role for lck activity in determining the threshold for differentiation of the CD4 lineage is revealed in experiments with thymi deficient for a regulator of lck activity, CD45. A model of thymocyte differentiation is presented in which we propose that the relative balance of signals delivered by TCR engagement and lck activation determines lineage choice.

Animals↗

PubMed2026

Identification of lineage-associated polymorphisms in the ROP18 3' flanking region and development of molecular assays for differentiation of Toxoplasma gondii lineages.

BACKGROUND: Toxoplasma gondii (T. gondii) exhibits substantial genetic diversity, and different parasite lineages are associated with distinct epidemiological distributions and biological characteristics. Accurate molecular characterization of T. gondii strains is important for understanding parasite population structure and transmission patterns. However, existing genotyping approaches often require multiple loci, extensive experimental procedures, or complex data analysis. Therefore, simplified and reliable molecular markers for rapid lineage differentiation are still needed. METHODS: In this study, comparative genomic analysis was performed using representative T. gondii strains with well-defined genetic backgrounds and virulence phenotypes. The ROP18 genomic region, including partial genomic sequences, 5' flanking regions, coding sequence (CDS), and 3' flanking regions, was analyzed to identify informative polymorphic signatures. A short conserved sequence region containing lineage-associated polymorphic sites was identified within the ROP18 3' flanking region. Based on these sequence signatures, HRM-PCR and TaqMan MGB probe-based real-time PCR assays were developed and evaluated using plasmid standards and representative T. gondii genomic DNA samples. RESULTS: Phylogenetic analyses based on different ROP18 genomic regions demonstrated distinct clustering patterns among analyzed strains. Although the ROP18 3' flanking region was highly conserved, a short conserved sequence region containing informative polymorphic sites was identified, and the combination of these sites generated three distinct lineage-associated ROP18 patterns. Analysis of publicly available genomic datasets further demonstrated that individual strains contained one of these defined patterns rather than multiple patterns simultaneously. The developed HRM-PCR assay successfully discriminated the three ROP18-associated patterns based on distinct melting profiles with good reproducibility. Furthermore, the TaqMan MGB probe-based assay enabled specific identification of different ROP18-associated patterns through defined probe-recognition combinations and showed good analytical performance. CONCLUSION: This study identifies novel lineage-associated molecular signatures within the ROP18 3' flanking region and establishes complementary HRM-PCR and TaqMan MGB probe-based approaches for rapid molecular differentiation of T. gondii strains. These findings highlight the potential of conserved non-coding regions adjacent to functionally important genes as informative targets for parasite genotyping and provide a practical complementary tool for epidemiological surveillance and strain characterization.

HRM-PCR↗

PubMed2003

Recent divergence of the HLA-DRB104 allelic lineage from the DRB10701 lineage after the separation of the human and chimpanzee species.

Conventional phylogenetic trees for the human leukocyte antigen (HLA)-DRB1 alleles constructed by the neighbor-joining (Saitou and Nei 1987) and UPGMA (Sneath and Sokal 1973) methods using nucleotide sequences of the DRB1 alleles suggest that DRB1*0701 may have diverged from other DRB1 alleles before the separation of the human and chimpanzee species, because of a large number of nucleotide changes in DRB1*0701 compared with any of the other DRB1 alleles. Here we show new evidence that the haplotypes centering on DRB1*0701 and DRB1*04 alleles are the most homologous. This suggests that these haplotypes have derived from the common ancestral haplotype, and that they have likely retained complete linkage disequilibrium even after the divergence of the DRB1*0701 and DRB1*04 allelic lineages. Together with the corresponding haplotype carrying chimpanzee DRB1*0701, which has a high sequence homology to HLA-DRB1*0701, these haplotypes reveal that: (1) the DRB1*04 allelic lineage may have been generated from the DRB1*0701 lineage after the separation of the human and chimpanzee species; (2) the DRB1*04 allelic lineage possibly has a higher substitution rate of DRB1 compared with pseudogene and neutral region; (3) there could be a significant difference in the substitution rate of DRB1 between the DRB1*0701 and DRB1*04 allelic lineages. Based on the difference between the present and previous results, we would like to propose that phylogenetic studies using not only nucleotide sequences of the DRB1 alleles but also haplotypes centering on the alleles should be conducted for understanding detailed phylogenetic relationships of the DRB1 alleles.

Alleles↗

PubMed2006

Sau1: a novel lineage-specific type I restriction-modification system that blocks horizontal gene transfer into Staphylococcus aureus and between S. aureus isolates of different lineages.

The Sau1 type I restriction-modification system is found on the chromosome of all nine sequenced strains of Staphylococcus aureus and includes a single hsdR (restriction) gene and two copies of hsdM (modification) and hsdS (sequence specificity) genes. The strain S. aureus RN4220 is a vital intermediate for laboratory S. aureus manipulation, as it can accept plasmid DNA from Escherichia coli. We show that it carries a mutation in the sau1hsdR gene and that complementation restored a nontransformable phenotype. Sau1 was also responsible for reduced conjugative transfer from enterococci, a model of vancomycin resistance transfer. This may explain why only four vancomycin-resistant S. aureus strains have been identified despite substantial selective pressure in the clinical setting. Using a multistrain S. aureus microarray, we show that the two copies of sequence specificity genes (sau1hsdS1 and sau1hsdS2) vary substantially between isolates and that the variation corresponds to the 10 dominant S. aureus lineages. Thus, RN4220 complemented with sau1hsdR was resistant to bacteriophage lysis but only if the phage was grown on S. aureus of a different lineage. Similarly, it could be transduced with DNA from its own lineage but not with the phage grown on different S. aureus lineages. Therefore, we propose that Sau1 is the major mechanism for blocking transfer of resistance genes and other mobile genetic elements into S. aureus isolates from other species, as well as for controlling the spread of resistance genes between isolates of different S. aureus lineages. Blocking Sau1 should also allow genetic manipulation of clinical strains of S. aureus.

Bacterial Proteins↗

PubMed1997

Clinical features and treatment outcome of childhood T-lineage acute lymphoblastic leukemia according to the apparent maturational stage of T-lineage leukemic blasts: a Children's Cancer Group study.

PURPOSE: Leukemic cells from T-lineage acute lymphoblastic leukemia (ALL) patients are thought to originate from T-lymphocyte precursors corresponding to discrete stages of T-cell ontogeny. Here we sought to determine the influence of leukemic cell apparent maturational stage on treatment outcomes in pediatric T-lineage ALL. PATIENTS AND METHODS: From 1983 through 1993, 407 pediatric T-lineage ALL patients were enrolled onto two sequential series of risk-adjusted treatment protocols of the Children's Cancer Group. In the current analysis, T-lineage ALL patients were immunophenotypically classified as follows: CD7+ CD2- CD5- pro-thymocyte leukemia (pro-TL), CD7+ (CD2 or CD5)+ CD3- immature TL, and CD7+ CD2+ CD5+ CD3+ mature TL. RESULTS: Similar induction outcomes of 91.4%, 97.1%, and 98.3% were obtained by the pro-, immature, and mature TL groups, respectively. Four-year event-free survival (EFS) was lower for pro-TL patients (57.1%; SD = 8.4%,) compared with immature and mature TL patients (68.5%; SD = 3.5%; and 77.1%; SD = 4.0%, respectively) with an overall significance of .05 (log-rank test) or .04 (log-rank trend test). Relative hazards rates (RHR) were 2.11 and 1.22 for pro-TL and immature TL versus mature TL, respectively. Highly significant differences were found for overall survival (P = .005, log-rank test; P = .009, log-rank trend test). Multivariate analysis confirmed that the prognostic influence of ontogeny grouping was independent of that of other prognostic factors. CONCLUSION: Leukemic cells of the pro-TL maturation stage identify a small subgroup of T-lineage ALL patients who have a significantly worse EFS outcome than patients whose cells are of a more mature stage of development.

Analysis of Variance↗

PubMed1988

Lineage heterogeneity in acute leukemia with the t(4;11) abnormality: implications for acute mixed lineage leukemia.

Acute leukemia associated with the t(4;11)(q21;q23) abnormality demonstrates marked lineage heterogeneity, including cases with features of acute mixed lineage leukemia. We report 7 patients with acute leukemia with the t(4;11) abnormality in which we have defined the range of lineage commitment associated with this disease utilizing a variety of cell characterization techniques. Each case could be classified either as acute lymphoblastic leukemia (ALL) (5 cases) or acute myelogenous leukemia (AML) (2 cases) based on standard light microscopic criteria supplemented by ultrastructural determination of myeloperoxidase. Evidence for acute mixed lineage leukemia was found in one of the AML patients in which coexpression of CD14 and CD19 surface antigens was demonstrated. Overall, the findings further confirm the lineage heterogeneity previously reported in association with t(4;11) acute leukemia. The implications of the findings as to the pathogenesis of t(4;11) acute leukemia are discussed.

Adult↗

PubMed2006

Near-triploidy and near-tetraploidy in childhood acute lymphoblastic leukemia: association with B-lineage blast cells carrying the ETV6-RUNX1 fusion, T-lineage immunophenotype, and favorable outcome.

The prognostic significance of near-triploidy (68-80 chromosomes) and near-tetraploidy (>80 chromosomes) in childhood acute lymphoblastic leukemia (ALL) is unclear. Therefore, we retrospectively evaluated the incidence of and outcome associated with these subtypes of ALL. In 620 children with ALL diagnosed between 1988 and 1999, the leukemic cells were near-triploid (DNA index, 1.50-1.73) in 4 and near-tetraploid (DNA index, 1.79-2.28) in 14. Of 15 patients with B-lineage ALL, 11 (73.3%) had an ETV6-RUNX1 (previously TEL-AML1 and then ETV6-CBFA2) fusion. No differences in age (P = 0.99), leukocyte count (P = 0.99), or immunophenotype (P = 0.99) were observed between patients with near-triploidy and those with near-tetraploidy. Patients with near-triploidy or near-tetraploidy were more likely than those with high-hyperdiploidy (51-67 chromosomes) (n = 159) to be female (P = 0.05) and have T-lineage ALL (P = 0.02), L2 morphology (P < 0.0001), or the ETV6-RUNX1 fusion (P < 0.0001). The median follow-up period was 10.4 years. The 5-year event-free survival estimates (+/- SE) were 75% +/- 19% for patients with near-triploidy, 93% +/- 7% for those with near-tetraploidy, and 84% +/- 3% for those with high-hyperdiploidy. Although near-triploidy and near-tetraploidy are biologically different from high-hyperdiploidy, the favorable outcomes of patients with any one of these abnormalities suggest that patients with B-lineage ALL and a DNA index >or= 1.16 can be included in the low-risk arm of treatment protocols. We cannot make similar recommendations for patients with T-lineage ALL because of the small number of cases (n = 3) in this study.

B-Lymphocytes↗

PubMed1993

The close relationship between DNA replication and the selection of differentiation lineages of human erythroleukemia cell lines K562, HEL, and TF1 into either erythroid or megakaryocytic lineages.

The selection of differentiation lineages into either erythroid or megakaryocytic series was analyzed with human erythroleukemia cell lines K562, HEL, and cytokine-dependent TF1. A tumor promoter, TPA, induced a megakaryocyte marker, glycoprotein IIb/IIIa (GP IIb/IIIa) or IIIa (GP IIIa), but suppressed erythroid differentiation. On the other hand, aphidicolin, which is a potent inhibitor of DNA replication, inhibited GP IIb/IIIa or IIIa expression, but induced the expression of erythroid phenotypes. These phenomena were observed in all erythroleukemia cell lines tested. The bromodeoxyuridine labeling experiments indicated that de novo DNA synthesis was completely suppressed by aphidicolin treatment but was well preserved in TPA-treated cells. Among these three cell lines, erythropoietin (EPO) treatment induced erythroid differentiation of TF1 cells, which was dependent on GM-CSF or IL-3. In this case, EPO functioned as the survival factor and mild stimulator for cell proliferation as well as the inducer of erythroid differentiation. However, when either GM-CSF or IL-3 was depleted from the culture medium, TF1 ceased cell growth; concomitantly, hemoglobin-positive cells appeared, which is consistent with the results obtained with aphidicolin. The incubation of K562 cells for 48 h with either TPA or aphidicolin induced the irreversible commitment of cells to megakaryocytic and erythroid lineages, respectively. Our results using three different erythroleukemia cell lines suggest that a possible linkage between the DNA replication system and the selection of a differentiation lineage is the common feature of human erythroleukemia cell lines, and that these culture systems provide a suitable model for the analysis of the signal transduction system for differentiation lineage selection.

Aphidicolin↗

PubMed2003

Unrelated donor bone marrow transplantation for acute mixed lineage (myeloid and B-lymphoid lineage) leukemia in an adult with Down syndrome.

This article describes a rare case of bone marrow transplantation (BMT) from an unrelated donor (URD) in an adult Japanese male with Down syndrome (DS) diagnosed as having acute mixed lineage leukemia. Examination of peripheral blood demonstrated WBC 6.2 x 10(9)/l with 45.5% blasts at admission. Leukemic blasts with positive peroxidase stain, but negative periodic acid-Schiff stain comprised 91.6% on bone marrow specimen. Surface marker analysis of these blasts showed the following: CD3(-), CD5(-), CD7(-), CD10(+), CD19(+), CD13(+), CD14(-), CD33(+), CD34(+), CD41a(-), and CD56(-). Based on these data, he was diagnosed as having acute mixed lineage (myeloid and B-lymphoid lineage) leukemia. He achieved complete remission (CR) by lymphoid-oriented chemotherapy performed after ineffective myeloid-oriented therapy. After four courses of consolidation chemotherapy for lymphoid lineage blasts, recurrence due to proliferation of myeloblasts had occurred. Thereafter, a second CR was obtained by low dose cytosine arabinoside (AraC) therapy. As this patient was considered to have a high risk of relapse, we selected allogeneic BMT from URD. Severe stomatitis due to methotrexate (MTX) occurred probably due to altered pharmacokinetics usually observed in DS patients. Though acute graft-versus-host disease (GVHD) of systemic skin (grade II) and pneumonia were observed during neutropenia due to the post-conditioning regimen, he could be discharged from our hospital on the 135th day after BMT. On day 205 post-BMT, however, bronchiolitis obliterans (BO) occurred as a chronic GVHD disorder. Despite therapy with prednisolone and FK506, he died on day 400 post-BMT because of respiratory failure due to BO. In DS patients, superfluous toxicities due to MTX and AraC treatment have been reported, and these toxicities have been considered due to altered pharmacokinetics in patients with DS. This patient could tolerate the transplant conditioning regimen commonly used in patients without DS.

Adult↗

PubMed1997

Involvement of gene-specific DNA damage and apoptosis in the differential toxicity of mitomycin C analogs towards B-lineage versus T-lineage lymphoma cells.

Avian and mammalian B- and T-lineage lymphocytes display differential sensitivity to a variety of genotoxic agents. Specifically, T-lineage cells show a high degree of resistance to the toxic effects of exposure to chemotherapeutic drugs, whereas B-lineage cells show a high degree of sensitivity. We used a model system consisting of virally transformed B- and T-lymphoma cell lines to further define the cellular and molecular mechanisms responsible for the differential toxicity of two chemotherapeutic drugs that induce DNA-interstrand cross-links to different degrees, mitomycin C (MMC) and its aminodisulfide analog, BMY 25067. Quantification of the number of cross-links introduced in the transcriptionally active ribosomal RNA gene cluster revealed that similar levels of DNA damage were induced in B- and T-lymphoma cell lines. However, B-lymphoma cells were highly sensitive to induction of apoptosis and inhibition of growth compared with the more resistant T-lymphoma cells for both compounds. BMY 25067 induced approximately 2-fold more cross-links in rDNA than did MMC, along with a concurrent enhanced induction of apoptosis in both B- and T-lymphoma cell lines. An analysis of the persistence of DNA lesions over multiple cell cycles revealed that neither B- nor T-lymphoma cells repaired DNA cross-links to a significant extent. These data suggest that differences in the extent or persistence of DNA-interstrand cross-links are not responsible for the differential toxicity of MMC and its analog towards B- versus T-lineage cells. Rather, differential drug toxicity involves early and extensive entry into apoptosis in B-lymphoma cells contrasted to the delayed and minimal apoptotic induction in T-lymphoma cells.

Animals↗