Showing papers by "Todd R. Golub published in 1997"

Yolk sac angiogenic defect and intra-embryonic apoptosis in mice lacking the Ets-related factor TEL.

Abstract: The TEL gene, which is frequently rearranged in human leukemias of both myeloid and lymphoid origin, encodes a member of the Ets family of transcription factors. The TEL gene is widely expressed throughout embryonic development and in the adult. To determine the requirement for the TEL gene product in development we generated TEL knockout mice ( TEL −/− ) by gene targeting in embryonic stem cells. TEL −/− mice are embryonic lethal and die between E10.5–11.5 with defective yolk sac angiogenesis and intra‐embryonic apoptosis of mesenchymal and neural cells. Two‐thirds of TEL‐deficient yolk sacs at E9.5 lack vitelline vessels, yet possess capillaries, indicative of normal vasculogenesis. Vitelline vessels regress by E10.5 in the remaining TEL −/− yolk sacs. Hematopoiesis at the yolk sac stage, however, appears unaffected in TEL −/− embryos. Our findings demonstrate that TEL is required for maintenance of the developing vascular network in the yolk sac and for survival of selected cell types within the embryo proper.

Occurrence of TEL-AML1 fusion resulting from (12;21) translocation in human early B-lineage leukemia cell lines

Abstract: The recurrent (12;21)(p13;q22) translocation fuses the two genes TEL and AML1 that have previously been cloned from translocation breakpoints in myeloid leukemias. Using mainly reverse transcriptase-polymerase chain reaction (RT-PCR), the TEL-AML1 chimeric transcript has been observed in 22-27% of pediatric patients with acute lymphoblastic leukemia (ALL), in particular in the early B-lineage ALL subtype, making it the most common genetic lesion in these patients. The vast majority of acute myeloid leukemias, other ALL subtypes and even adults with early B-lineage ALL were TEL-AML1-negative. We determined whether the TEL-AML1 fusion gene can also be observed in continuous human leukemia cell lines with an early B-lineage phenotype. Twenty-nine such cell lines established from children (n = 13) or adults (n = 13) with early B-lineage ALL and five cell lines derived from chronic myeloid leukemia in blast crisis or B cell non-Hodgkin's lymphoma were investigated for the occurrence of the TEL-AML1 rearrangement by RT-PCR. While all 13 adult early B-lineage ALL cell lines and the five cell lines from other leukemias or lymphomas were negative, 1/13 pediatric cell lines (cell line REH) was found to be positive for TEL-AML1; though neither reciprocal AML1-TEL, nor normal TEL, mRNA was detectable by RT-PCR in this cell line. These findings agreed with the results of conventional cytogenetic and FISH analysis of REH which was found to carry the der(21) partner only of t(12;21)(p13;q22), probably resulting from a complex translocation, t(4;12;21;16)(q32;p13;q22;q24.3). Hybridization with flanking cosmid clones (179A6 and 148B6), covering exons 1 and 8 respectively of TEL, confirmed a rearrangement accompanying the t(12;21), and showed cryptic deletion of the residual allele resulting from an apparently reciprocal t(5;12)(q31;p13). These findings in REH provide a further example of, and possible cytogenetic mechanism for, the paradigm of TEL-AML1 fusion accompanied by deletion of the residual TEL allele. The low rate of early B-lineage ALL cell lines carrying this translocation contrasts clearly with the relative high frequency of TEL-AML1-positive cases in primary material. It is possible that expression of the fusion product hampers the in vitro growth and establishment in culture of such leukemic cells. Nevertheless, the cell line REH represents a powerful tool for the further molecular characterization of this unique breakpoint and can serve as a positive control in routine PCR reactions.

The TEL Gene Contributes to the Pathogenesis of Myeloid and Lymphoid Leukemias by Diverse Molecular Genetic Mechanisms

Abstract: The TEL gene, originally cloned by virtue of involvement in the t(5;12) chromosomal translocation associated with chronic myelomonocytic leukemia (CMML), has a remarkable capacity to contribute to the pathogenesis of human leukemias: (1) TEL has been implicated in both myeloid and lymphoid leukemias, acute and chronic leukemias, and leukemias of both pediatric and adult populations; (2) TEL can contribute either its DNA binding domain or a putative helix-loop-helix (HLH) domain to fusion proteins, and (3) TEL has been associated with a surprising variety of fusion partners in human leukemias, including genes for transcription factors, receptor and non-receptor tyrosine kinases, and putative transcriptional activating domains. In addition, recent evidence suggests that loss of function of TEL may also contribute to pathogenesis of malignancy. In this report, the diverse molecular genetic mechanisms of leukemogenesis mediated by the TEL gene will be discussed.

TEL is one of the targets for deletion on 12p in many cases of childhood B-lineage acute lymphoblastic leukemia

Abstract: Abnormalities of the short arm of chromosome 12 including loss of heterozygosity (LOH) and TEL/AML-1 fusion resulting from a t(12;21)(p13;q22) translocation are frequently observed in childhood acute lymphoblastic leukemia (ALL). We investigated 21 DNA samples of childhood ALL which had LOH at 12p13. Rearrangement of TEL was observed in eight cases and another case showed a homozygous deletion of TEL. Two informative samples with TEL rearrangement had a deletion localized to the 5' region of this gene. The deletion in these two cases includes the helix-loop-helix (HLH) domain. This is consistent with the hypothesis that the normal tel can heterodimerize with the TEL/AML-1 gene product and inhibit the transforming capacity of the chimeric protein. Presumably, loss of the HLH of the normal remaining TEL allele abrogates this tumor suppressor-like function. The case with homozygous deletion of TEL is also consistent with this gene having qualities of a tumor suppressor. One unusual case had T-ALL rather than B-lineage ALL and the leukemic cells had rearrangement of TEL, but they did not have an alteration of the remaining TEL allele suggesting that the etiology of this disease may be different. This analysis further emphasizes the importance of loss of the normal TEL allele in childhood precursor B-lineage ALL.

Tel gene rearrangements in myeloid malignancy

Abstract: The molecular pathogenesis of human myeloid malignancy is being elucidated as the genetic abnormalities that are consistently associated with it are identified. Whereas the lymphoid leukemias are typified by overexpression of structurally normal genes as a result of juxtaposition with highly recombinogenic enhancer elements such as the immunoglobulin heavy-chain locus, the myeloid leukemias are more commonly associated with the formation of chimeric proteins as a consequence of chromosomal translocation. It is becoming clear that although there is an expanding list of different chromosomal translocations associated with particular leukemias, a limited number of genes (or pathways) are targeted by these translocations. For example, the t(8;21), t(3;21), and inv(16) translocations in acute myeloid leukemia (AML) all disrupt components of the transcription factor complex core binding. 6,21,23,24,26,27 Similarly, while there are over 30 different chromosomal translocations involving chromosome band 11q23, the vast majority of these disrupt a single intron within the MLL gene, suggesting that dysregulation of MLL function is common to all of these rearrangements. 48 A more recently described "promiscuous" gene in both myeloid and lymphoid malignancy is the TEL gene (also known as ETV6 ). As discussed subsequently, the TEL gene is unusual because there may be more than one mechanism by which its rearrangement through chromosomal translocation is leukemogenic.