MLL-AF4 gene fusions in normal newborns.
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Bone Marrow↗
Biomedical subjects
M F Greaves
Publications and source records attributed to M F Greaves.
[Adult T cell leukemia lymphoma in Chile. A clinical pathologic and molecular study of 26 patients].
BACKGROUND: Adult T cell leukemia lymphoma is a lymphoproliferative syndrome etiologically associated to human T cell lymphotropic virus type I. AIM: To describe the clinical and laboratory features of 26 Caucasian Chilean patients, with HTLV-I positive adult T-cell leukemia lymphoma (ATLL). MATERIAL AND METHODS: Diagnostic criteria included clinical features, cell morphology, immunophenotype, HTLV-I serology and/or DNA analysis by Southern blot or PCR. RESULTS: According to the clinical presentation, 12 cases had the acute ATLL form, 6 had a lymphoma, 4 the chronic form and 4 had smoldering ATLL. The median presentation age was 50 years, younger than the Japanese patients, but significantly older than patients from other South American countries (e.g. Brasil, Jamaica, Colombia). The main clinical features: lymphadenopathy, skin lesions and hepatosplenomegaly, were similar in frequency to those of patients from other countries, except for the high incidence of associated neurological disease. Tropical Spastic Paraparesis (TSP) in our series of ATLL, was seen in one third of the patients (8/26). A T-cell immunophenotype was shown in all 26 cases and HTLV-I serology was positive in 25/26 patients. Molecular analysis on the seronegative patient showed clonal integration of proviral HTLV-I DNA into the lymphocytes DNA, and thus he may have been a poor responder to the retroviral infection. Proviral DNA integration was also demonstrated in 15/16 patients being clonal in 10, polyclonal in 3 (all smoldering cases) and oligoclonal in one. CONCLUSIONS: ATLL in Chile has similar clinical and laboratory features than the disease in other parts of the world, except for a younger age than Japanese patients but older than those from other Latin American countries and a high incidence of patients with associated TSP. Detailed morphological and immunophenotypic analysis of the abnormal circulating lymphocytes, together with the documentation of HTLV-I by serology and/or DNA analysis are key tests for the identification of this disease.
Acute Disease↗
Ionising radiation and leukaemia potential risks: review based on the workshop held during the 10th Symposium on Molecular Biology of Hematopoiesis and Treatment of Leukemia and Lymphomas at Hamburg, Germany on 5 July 1997.
Unexplained clusters of childhood leukaemia have generated concern that they may be causally related to environmental exposure to ionising radiation. The workshop provides in-depth examination of the aetiology of childhood leukaemia, patterns of clustering exhibited by cases and the influence of exposure to ionising radiation. Special attention has been focussed on the EUROCLUS study of clustering of childhood leukaemia and monitoring of populations exposed to contamination following the Chernobyl accident. There is insufficient evidence to conclude that environmental ionising radiation exposure is a causative agent for small clusters such as that reported in the vicinity of the Krümmel nuclear facility
Child↗
Backtracking leukemia to birth: identification of clonotypic gene fusion sequences in neonatal blood spots.
Epidemiological evidence has suggested that some pediatric leukemias may be initiated in utero and, for some pairs of identical twins with concordant leukemia, this possibility has been strongly endorsed by molecular studies of clonality. Direct evidence for a prenatal origin can only be derived by prospective or retrospective detection of leukemia-specific molecular abnormalities in fetal or newborn samples. We report a PCR-based method that has been developed to scrutinize neonatal blood spots (Guthrie cards) for the presence of numerically infrequent leukemic cells at birth in individuals who subsequently developed leukemia. We demonstrate that unique or clonotypic MLL-AF4 genomic fusion sequences are present and detectable in neonatal blood spots from individuals who were diagnosed with acute lymphoblastic leukemia at ages 5 months to 2 years and, therefore, have arisen during fetal hematopoiesis in utero. This result provides unequivocal evidence for a prenatal initiation of acute leukemia in young patients. The method should be applicable to other fusion genes in children with common subtypes of leukemia and will be of value in attempts to unravel the natural history and etiology of this major subtype of pediatric cancer.
Artificial Gene Fusion↗
Aetiology of acute leukaemia.
Ionising radiation, in high dose and with acute exposure, is a factor that has been implicated in leukaemogenesis, but what is the evidence for leukaemogenesis and exposure to diagnostic X-rays, to natural terrestrial or cosmic ionising radiation, to electromagnetic fields, or to nuclear energy? Why is population mixing and infection a possible explanation for the clusters of childhood acute leukaemias around the nuclear processing plants of Sellafield and Dounreay? These questions, as well as how chemical agents, including therapeutic substances, might contribute to leukaemogenesis, are discussed in this last article in the leukaemia series.
Acute Disease↗
Clustering of childhood leukaemia in Hong Kong: association with the childhood peak and common acute lymphoblastic leukaemia and with population mixing.
Incidence data of childhood leukaemia (CL) in Hong Kong (1984-90) have been analysed for evidence of variation between small areas. All cases (n=261) were classified by morphological cell type, with the majority (n=205) being acute lymphoblastic leukaemia (ALL), and haematological review has permitted immunophenotypic classification for 73% of these. The data have been examined for evidence of spatial clustering within small census areas (TPUs) and for association with population mixing, with attention focused on those subgroups (especially the childhood peak of ALL--taken here to be diagnoses in children from 24 months up to the seventh birthday--and common ALL) which, it has been hypothesized, may be caused by unusual patterns of exposure and response to common infections. For the whole of Hong Kong, there was evidence of spatial clustering of ALL at ages 0-4 years (P = 0.09) and in the childhood peak (P<0.05). When these analyses were restricted to TPUs where extreme population mixing may have occurred, overall incidence was elevated and significant evidence of clustering was found for ALL (P<0.007) at these ages and for the common ALL in the childhood peak (P = 0.032). Replication of the analyses for subsets of leukaemia that were not dominated by the childhood peak of ALL found no evidence of clustering. This is the first investigation of an association between population mixing and childhood leukaemia in Asia and the first to include clustering and to consider particular subsets. The results are supportive of the 'infectious' aetiology hypothesis for subsets of childhood leukaemia, specifically common ALL in the childhood peak.
Adolescent↗
ts BCR-ABL kinase activation confers increased resistance to genotoxic damage via cell cycle block.
Using a temperature-sensitive mutant of the p210 BCR-ABL gene, transfected into a growth factor-dependent cell line (BaF3), we show that transient BCR-ABL kinase expression increases single cell and clonogenic resistance to apoptosis arising from genotoxic damage induced by ionizing radiation and VP-16/etoposide. This effect is achieved in the absence of any detectable changes in the levels of BCL-2, BAX or BCL-x proteins and is independent of proliferative, MAP kinase-dependent effects of BCR-ABL kinase. In contrast to parental cells that transiently arrest in G2 and then apoptose, p210 BaF3 cells show a pronounced and sustained G2 arrest following radiation coupled with enhanced phosphorylation of cdc2. A cell cycle block in early M phase induced by the mitotic spindle poison, nocodazole, does not provide protection from apoptosis. Reversal of G2 arrest by caffeine abolishes the protective effect of BCR-ABL kinase. These data provide further insight into the transforming properties of BCR-ABL and are relevant to the clinical intransigence of Ph-positive leukaemias.
Antineoplastic Agents, Phytogenic↗
Regulation of the myeloperoxidase enhancer binding proteins Pu1, C-EBP alpha, -beta, and -delta during granulocyte-lineage specification.
We have compared the molecular architecture and function of the myeloperoxidase upstream enhancer in multipotential versus granulocyte-committed hematopoietic progenitor cells. We show that the enhancer is accessible in multipotential cell chromatin but functionally incompetent before granulocyte commitment. Multipotential cells contain both Pu1 and C-EBP alpha as enhancer-binding activities. Pu1 is unphosphorylated in both multipotential and granulocyte-committed cells but is phosphorylated in B lymphocytes, raising the possibility that differential phosphorylation may play a role in specifying its lymphoid versus myeloid functions. C-EBP alpha exists as multiple phosphorylated forms in the nucleus of both multipotential and granulocyte-committed cells. C-EBP beta is unphosphorylated and cytoplasmically localized in multipotential cells but exists as a phosphorylated nuclear enhancer-binding activity in granulocyte-committed cells. Granulocyte colony-stimulating factor-induced granulocytic differentiation of multipotential progenitor cells results in activation of C-EBP delta expression and functional recruitment of C-EBP delta and C-EBP beta to the nucleus. Our results implicate Pu1 and the C-EBP family as critical regulators of myeloperoxidase gene expression and are consistent with a model in which a temporal exchange of C-EBP isoforms at the myeloperoxidase enhancer mediates the transition from a primed state in multipotential cells to a transcriptionally active configuration in promyelocytes.
Animals↗
Infant leukaemia biology, aetiology and treatment.
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Chromosomes, Human, Pair 11↗
[Immunophenotype. Clinical and laboratory features of acute lymphoblastic leukemia in Chile. Study of 500 children and 131 adults].
We describe the clinical features and immunophenotype of 500 children and 131 adults with acute lymphoblastic leukemia (ALL), diagnosed between 1984 and 1993. Cases were classified, according to immunophenotype in B-cell ALL with three subtypes (pro-B or null, common and B) and T-cell ALL. Among children, common ALL accounted for 74% of cases and pro-B all was more common in children of less than one year (14%). B ALL was observed in 2% of children. Ten percent of children, mostly males, had T-cell ALL. The third part of these children had high leukocyte counts and a mediastinal mass. Children from Mapuche origin, compared with Caucasian children had a lower proportion of common ALL (36 and 74% respectively) and a higher proportions of T-cell ALL (41 and 10% respectively). Among adults common ALL was the most common phenotype (72%) followed by T-cell ALL (15%), pro-B ALL (11%) and B-cell ALL (2%). There was a lower incidence of children with common ALL with positive cytoplasmic immunoglobulin compared to North American or European studies (2 and 15-33% respectively) and a higher proportion of adults with common ALL compared with pro-B cell ALL, in contrast to European studies that show a higher proportion of patients with pro-B cell ALL. No other immunophenotypic, clinical or laboratory differences were observed with ALL from developed countries. It is concluded that the immunophenotyping of ALL allows a more precise diagnosis of this disease.
Adolescent↗
Intrauterine monoclonal origin of neonatal concordant acute lymphoblastic leukemia in monozygotic twins.
We report detailed immunological, cytogenetic and molecular evidence for complete identity of the leukemic cell populations in monozygotic female twins with concordant leukemia diagnosed at two months of age. Both infants had early pre-B acute lymphoblastic leukemia with the (11;19)(q23;p13) chromosomal translocation. A common clonal origin of leukemia in these infants was suggested by the finding of identical oligoclonal heavy chain immunoglobulin gene rearrangements. Leukemic cell DNA was examined for 11q23 rearrangements by Southern blotting and restriction fragments of identical size were found in the two cases, in contrast to the diversity of rearrangements observed in other unrelated and nontwinned control infants with t(11;19)(q23;p13). Similar restriction fragments were absent in blood mononuclear DNA from both parents, liver tissue from one twin and remission bone marrow of the other, indicating that the 11q23 rearrangement was acquired and not inherited as a chromosomal abnormality or polymorphism. These findings provide a definitive evidence for intrauterine single cell origin, with twin to twin transmission, of concordant leukemia in this infant twin pair.
Blotting, Southern↗
HTLV-I positive progressive spastic paraparesis (TSP) associated with a lymphoid disorder in three Chilean patients.
We describe the clinical and laboratory features in three Caucasian Chilean patients with tropical spastic paraparesis (TSP) associated with/or preceded by a lymphoproliferative disorder involving cutaneous lesions and localised lymphadenopathy. The neurological symptoms and signs were characteristic of TSP and CSF examination revealed the presence of oligoclonal bands. All three patients had a moderate leucocytosis (10-14 x 10(9)/l) with eosinophilia and a minority (2-4%) of circulating atypical polylobed or ATLL-like lymphocytes. Lymph node histology showed a diffuse pattern of infiltration (1 case) and marked expansion of the paracortical zone with convoluted lymphocytes and immunoblasts (2 cases). Skin biopsy demonstrated a dermal lymphoid infiltration with epidermotropism. Antibodies to HTLV-I were detected in the serum and CSF in the three patients and Southern blot analysis of peripheral blood mononuclear cells showed a monoclonal integration of HTLV-I proviral DNA in one case whereas in the two others the pattern was indicative of low level polyclonal integration. All three patients were treated with prednisolone and one with PUVA with transient partial response on the skin and neurological manifestations. Two patients died months to 5 years from presentation and the other is alive 12 years from diagnosis with active neurological and skin disease. The simultaneous occurrence of HTLV-I associated TSP with smouldering ATLL and a cutaneous ATLL or pre-leukaemic form is discussed.
Adult↗
Request for leukaemic samples from twins.
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Child↗
Rapid intraclonal switch of lineage dominance in congenital leukaemia with a MLL gene rearrangement.
We describe a case of neonatal mixed lineage leukaemia which presented with a dominant B progenitor lymphoblast population plus a minor monocytic component. Treatment of the patient with corticosteroid and Ara-C resulted in loss of lymphoblasts and a rapid (within 7 days) increase and dominance of the monocytic component. The common clonal origin of the two cell types was evident from the identical rearrangement in the MLL gene and a shared rearrangement of one IGH allele. In common with other neonatal or infant ALL with MLL gene rearrangements, this leukaemia may have originated in a common B-monocytic lineage stem cell during foetal haemopoiesis. The observations further suggest that the therapeutic impact of the MLL gene rearrangement is to some extent dependent on the cellular context in which it is expressed.
DNA-Binding Proteins↗
Lethality and mutagenesis of B lymphocyte progenitor cells following exposure to alpha-particles and X-rays.
B lymphocyte precursor cells are the target cells for the major subtype of paediatric cancer, acute lymphoblastic leukaemia. Using a murine IL-7-dependent clonogenic assay for normal B cell precursors as a model, we have investigated the sensitivity of these cells versus other normal and leukaemic haemopoietic cells to alpha-particle radiation. We find that B cell precursors are remarkably susceptible to the lethal effects of alpha-particles and have a very low probability of surviving a single alpha-track. B cell precursors are also very sensitive to the lethal effects of low LET X-rays. The mutation frequency in a marker gene (HPRT) does not, however, appear to be greater in B cell precursors that survive X-radiation than in other haemopoietic cells.
Alpha Particles↗
Clustering of human T lymphotropic virus type I seropositive in Montserrat, West Indies: evidence for an environmental factor in transmission of the virus.
A community survey of human T cell lymphotropic virus type I (HTLV-I) in Montserrat, West Indies, identified 22 instances in which 2 HTLV-I-seropositive adults lived within 60 m of each other (close pairs), compared with 7.8 expected (P < .001). Five of these close pairs were mother-offspring or husband-wife. The remaining 17 pairs were of unrelated members in separate households. The percentages of male-female (41%), female-female (41%), and male-male (18%) types in these 17 pairs were very similar to those among the 1377 similarly defined pairs in which neither or only 1 member was seropositive, affording no support for extramarital heterosexual activity as an explanation for the clustering observed. Thus, the demography of HTLV-I was not accounted for completely by sexual and mother-to-offspring transmission. The predominance of clustering of unrelated HTLV-I-seropositive individuals in locations with high mosquito infestation raised the possibility of sporadic transmission of HTLV-I by hematophagous insects.
Adolescent↗
Apoptosis in carcinogenesis: the role of p53.
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Aneuploidy↗
Lack of MDM2 amplification in human leukaemia.
While deletion or mutation of the p53 gene is one of the most common molecular alterations detected in a wide variety of tumours, it has been shown to occur in only a relatively small percentage of the leukaemia cases examined. However, it may be that other components of the p53 pathway are involved. Amplification of the MDM2 gene has recently been demonstrated in human sarcomas resulting in an increase in MDM2 protein levels. This protein can bind to p53 preventing the transactivation of p53 responsive genes, thus mimicking mutation or deletion of p53. We have investigated the prevalence of MDM2 amplification in human leukaemias. 101 leukaemia or lymphoma samples and nine cell lines were studied using Southern blotting. In no case was MDM2 amplification present. We conclude that MDM2 amplification is not a common event in human leukaemias.
Blotting, Southern↗