EBP1, a novel host factor involved in primer binding site-dependent restriction of moloney murine leukemia virus in embryonic cells.

Mouse embryonic cells are unable to support the replication of Moloney murine leukemia virus (MLV). The integrated viral DNA is transcriptionally silenced, largely due to binding of host transcriptional repressors to the primer binding site (PBS) of the provirus. We have previously shown that a PBS DNA-binding repressor complex contains ZFP809 and TRIM28. Here, we identified ErbB3-binding protein 1 (EBP1) to be a novel component of the ZFP809-TRIM28 silencing complex and show that EBP1 depletion reduces PBS-mediated retroviral silencing.

Mirror syndrome associated with fetal leukemia.

Mirror syndrome describes the association of fetal and placental hydrops with maternal edema. This case is the first reported case of mirror syndrome relative to fetal leukemia. We suggest that fetal leukemia can have a major impact on mirror syndrome, and provide a brief review of the literature related to this syndrome.

Mutation accumulation and developmental lineages in normal and Down syndrome human fetal haematopoiesis.

Children show a higher incidence of leukemia compared to young adolescents, yet their cells have less age-related (oncogenic) somatic mutations. Newborns with Down syndrome have an even higher risk of developing leukemia, which is thought to be driven by mutations that accumulate during fetal development. To characterize mutation accumulation in individual stem and progenitor cells of Down syndrome and karyotypically normal fetuses, we clonally expanded single cells and performed whole-genome sequencing. We found a higher mutation rate in haematopoietic stem and progenitor cells during fetal development compared to the post-infant rate. In fetal trisomy 21 cells the number of somatic mutations is even further increased, which was already apparent during the first cell divisions of embryogenesis before gastrulation. The number and types of mutations in fetal trisomy 21 haematopoietic stem and progenitor cells were similar to those in Down syndrome-associated myeloid preleukemia and could be attributed to mutational processes that were active during normal fetal haematopoiesis. Finally, we found that the contribution of early embryonic cells to human fetal tissues can vary considerably between individuals. The increased mutation rates found in this study, may contribute to the increased risk of leukemia early during life and the higher incidence of leukemia in Down syndrome.

Backtracking of leukemic clones to birth.

Many of the acquired genetic changes that contribute to the molecular pathogenesis of leukemia are well characterized. The relative simplicity of the tumor genetics of the common subtypes of leukemia and the availability of archived material in the form of archived neonatal blood spots (ANB or Guthrie cards) has permitted the tracing of many genetic events to fetal origins using sensitive amplification methods. We here described methods for cloning translocations and other rearrangements for "backtracking" studies, and methods for sensitive detection of such rearrangements and a point mutation in ANB cards.

Prognostic relevance of ALL-1 gene rearrangement in infant acute leukemias.

We and others have recently reported a high frequency (70-80%) of ALL-1 (MLL, HRX, HTRX) gene rearrangements in infants with acute leukemias (AL) aged less than 1 year. Preliminary observations in limited series also suggested that ALL-1 gene configuration is an important prognostic factor in this leukemic subset. We have now extended our study to a series of 45 AL patients aged between 0 and 18 months. The genomic configuration of ALL-1 in leukemic DNAs was determined by Southern blot hybridization and correlated with biological and clinical features at presentation, as well as with treatment outcome. Twenty-nine out of 45 (64%) patients showed ALL-1 rearrangements, including 4/11 (36%) infants aged between 13 and 18 months. Considering morphological types, 24/38 cases with acute lymphoblastic leukemia and 5/7 patients with acute myeloid leukemia showed ALL-1 rearrangements. The features more frequently found in association with ALL-1 rearrangements were hyperleukocytosis (P < 0.007) and CD19+/CD10- blast immunophenotype (P < 0.02). ALL-1 status was an independent prognostic marker of event-free survival (EFS) in a multivariate model including age, sex and WBC count, and maintained its statistical significance when FAB morphology was considered in the analysis by including AML patients. Considering the ALL cases the actuarial EFS was 57 and 9% for infants with germline and rearranged ALL-1 configuration, respectively (P = 0.008). A high frequency of ALL-1 gene alterations in infant AL is confirmed by this study. In addition, our results emphasize the need for extending the analysis of ALL-1 gene status to infants with AL aged > 12 months. We show that this genetic lesion is the most important variable negatively affecting prognosis in a multivariate model including other known risk factors. This latter observation should influence the choice of risk-adapted treatment strategies in this AL subset.

Childhood leukaemia and exposure to pesticides: results of a case-control study in northern Germany.

The association between childhood leukaemia and exposure to pesticides was examined in a population-based case-control study conducted in Lower Saxony, Northern Germany. Between July 1988 and June 1992, 219 newly diagnosed cases were identified, of whom 173 participated in the study. Two sex- and age-matched control groups were recruited: local controls from the same communities as the newly diagnosed cases of leukaemia and state controls from other randomly selected communities in Lower Saxony. An additional study group consisted of 175 cases of solid tumours. When the leukaemia cases were compared with the local controls, positive associations with parental occupational exposure, particularly agriculture-related exposure, were observed, which were statistically non-significant. A significant association was found for pesticide use in gardens (odds ratio = 2.52, 95% confidence interval: 1.0-6.1). No positive associations were seen when the leukaemia cases were compared to the state controls, but this finding could be explained by a higher proportion of state controls living in rural areas. In communities with a significantly elevated standardised incidence ratio of childhood leukaemia over the last decade (1984-1993), the prevalence of pesticide use in the garden was 21%, compared with the 10% in other communities. None of the examined risk factors were more common among cases of solid tumours. Our findings add some evidence to the hypothesis that pesticides are a risk factor for childhood leukaemia, and there are good reasons to consider abundant pesticide use in rural areas as a possible cause for clustering of childhood leukaemia.

Pre-natal origins of childhood leukemia.

Chimeric fusion genes derived by chromosome translocation provide stable, sensitive and clone-specific markers for tracking the origins of leukemic cells and the natural history of disease and have been particularly informative in studies with twins concordant for leukemia and in retrospective scrutiny of archived neonatal blood spots. These data have indicated that in pediatric leukemia the majority, but not all, of the chromosome translocations arise, in utero, during fetal hemopoiesis, probably as initiating events. In most cases, functionally complementary and secondary genetic events are also required. These are acquired rapidly, and possibly in utero also, in infant acute lymphoblastic leukemia (ALL) but post-natally for most childhood ALL and acute myeloblastic leukemia (AML). An important consequence of the latter is a very variable and occasionally protracted post-natal latency (1-15 years). Another important corollary is that functional chromosomal translocations and pre-leukemic clones arise at a substantially higher frequency (approximately 100x) before birth than the cumulative incidence or risk of disease. These natural histories provide an important framework for consideration of key etiological events in pediatric leukemia.

Congenital syndromes and leukemia: clues to pathogenesis.

The association of specific congenital syndromes with leukemia provides an opportunity to study the process of leukemogenesis on the background of known genetic alterations. The role of the intracellular DNA damage response system in suppressing leukemia is demonstrated by the congenital disorders of genomic instability. Specific collaborations between survival and differentiation pathways characterize the leukemias observed in Down, Noonan and neurofibromatosis syndromes. As these syndromes clearly reveal, childhood leukemia arises when the delicate balance between growth, development and differentiation of the fetal and early post-natal hematopoietic system is disrupted.

Zebrafish as a model for the study of human cancer.

Zebrafish provide an exciting animal model system for the study of human cancers. During the last few years many zebrafish models of cancer have been generated that recapitulate human hematologic malignancies and solid tumors. Concurrent technological advances have significantly improved the genetic tractability and unique advantage of in vivo imaging in zebrafish, providing a means to dissect the molecular pathways underlying tumor initiation, progression and metastasis. Comparisons of cancer-associated gene expression profiles have demonstrated a high degree of similarity in the gene signatures of specific types of tumor cells in fish and humans, indicating that the contributing genetic pathways leading to cancer are evolutionarily conserved. Furthermore, the high fecundity, optical clarity and small embryo size of zebrafish continue to make it particularly amenable to performing whole-organism small molecule screens to identify targets for therapeutic development. This chapter reviews a wide array of these zebrafish cancer models and illustrates the advantages of the zebrafish system for exploring the molecular mechanisms governing cancer-related cellular processes.

[Fetal hepatosplenomegaly in the third trimester: A sign of leukemia in fetuses with Down syndrome]. / Hépatosplénomégalie fœtale au troisième trimestre : un signe d'appel de leucémie chez les fœtus porteurs de trisomie 21.

Risk for leukemic conditions increases in individuals with Down syndrome. We report a third trimester antenatal diagnosis of leukemia in a Down syndrome fetus. The third trimester ultrasound examination revealed a hepatosplenomegaly, which may suggest a myelopoiesis disorder. A review of the literature of eight cases described antenatally and 14 cases in the immediate neonatal period is presented.

Chromosome translocations and covert leukemic clones are generated during normal fetal development.

Studies on monozygotic twins with concordant leukemia and retrospective scrutiny of neonatal blood spots of patients with leukemia indicate that chromosomal translocations characteristic of pediatric leukemia often arise prenatally, probably as initiating events. The modest concordance rate for leukemia in identical twins ( approximately 5%), protracted latency, and transgenic modeling all suggest that additional postnatal exposure and/or genetic events are required for clinically overt leukemia development. This notion leads to the prediction that chromosome translocations, functional fusion genes, and preleukemic clones should be present in the blood of healthy newborns at a rate that is significantly greater than the cumulative risk of the corresponding leukemia. Using parallel reverse transcriptase-PCR and real-time PCR (Taqman) screening, we find that the common leukemia fusion genes, TEL-AML1 or AML1-ETO, are present in cord bloods at a frequency that is 100-fold greater than the risk of the corresponding leukemia. Single-cell analysis by cell enrichment and immunophenotype/fluorescence in situ hybridization multicolor staining confirmed the presence of translocations in restricted cell types corresponding to the B lymphoid or myeloid lineage of the leukemias that normally harbor these fusion genes. The frequency of positive cells (10(-4) to 10(-3)) indicates substantial clonal expansion of a progenitor population. These data have significant implications for the pathogenesis, natural history, and etiology of childhood leukemia.

Leukemia in twins: antenatal and postnatal factors.

Two factors emerged from a search for obstetric phenomena that might explain concordance of leukemia in both members of a twin pair within days or months of each other: antenatal exposure to ionizing radiation; and antenatal cojoined intrauterine circulation. In addition, antenatal tumor metastasis and chromosomal changes, antenatal or postnatal, may be contributory. Continued observation of reports should be carried out.