Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We cloned the t(10;14) recurrent translocation from CD3-negative T-cell acute lymphoblastic leukemia cells. The breakpoint at 14q11 involved an intermediate rearrangement of the delta T-cell receptor locus, suggesting that the translocation arose at the time of antigen receptor assemblage. Translocation introduced chromosome segment 10q24 as proven by hybridization of a breakpoint-derived probe to flow-sorted chromosomes and metaphase chromosomes. Two t(10;14) breakpoints were clustered within a 600-base-pair region of 10q24 but no heptamer-spacer-nonamer motifs resembling T-cell receptor/immunoglobulin rearrangement signals were noted at the breakpoint. A locus distinct from terminal deoxynucleotidyltransferase was found at 10q24. Evolutionarily conserved regions surrounding the 10q24 breakpoint were examined for transcriptional activity. A region telomeric to the 10q24 breakpoint, expected to translocate to the der(14) chromosome, recognized an abundant 2.9-kilobase RNA in a t(10;14) T-cell leukemia. This locus was not active in a variety of other normal and neoplastic T cells, arguing that it was deregulated by the introduction of the T-cell receptor. This locus is a candidate for a putative protooncogene, TCL3, involved in T-cell neoplasia.
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PMID:The t(10;14)(q24;q11) of T-cell acute lymphoblastic leukemia juxtaposes the delta T-cell receptor with TCL3, a conserved and activated locus at 10q24. 232 74

The T-cell receptor (TCR) alpha/delta chain locus on chromosome 14q11 is nonrandomly involved in translocations and inversions in human T-cell neoplasms. We have analyzed three acute T-lymphoblastic leukemia samples carrying a t(10;14)(q24;q11) chromosome translocation by means of somatic cell hybrids and molecular cloning. In all cases studied the translocation splits the TCR delta chain locus. Somatic cell hybrids containing the human 10q+ chromosome resulting from the translocation retain the human terminal deoxynucleotidyltransferase gene mapped at 10q23-q24 and the diversity and joining, D delta 2-J delta 1, regions of the TCR delta chain, but not the V alpha region (variable region of the TCR alpha chain), demonstrating that the split occurred within the V alpha-D delta 2 region. Molecular cloning of the breakpoint junctions revealed that the TCR delta chain sequences involved are made from the D delta 2 segment. The chromosome breakpoints are clustered within a region of approximately 263 base pairs of chromosome 10. The results suggest that the translocation of the TCR delta chain locus to a locus on 10q, which we have designated TCL3, results in deregulation of this putative oncogene, leading to acute T-cell leukemia.
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PMID:Clustering of breakpoints on chromosome 10 in acute T-cell leukemias with the t(10;14) chromosome translocation. 254 65

Human leukemic T cells carrying a t(10;14)(q24;q11) chromosome translocation were fused with mouse leukemic T cells, and the hybrids were examined for genetic markers of human chromosomes 10 and 14. Hybrids containing the human 10q+ chromosome had the human genes for terminal deoxynucleotidyltransferase that has been mapped at 10q23-q25 and for C alpha [the constant region of TCRA (the alpha-chain locus of the T-cell antigen receptor gene)], but not for V alpha (the variable region of TCRA). Hybrids containing the human 14q- chromosome retained the V alpha genes. Thus the 14q11 breakpoint in the t(10;14) chromosome translocation directly involves TCRA, splitting the locus in a region between the V alpha and the C alpha genes. These results suggest that the translocation of the C alpha locus to a putative cellular protooncogene located proximal to the breakpoint at 10q24, for which we propose the name TCL3, results in its deregulation, leading to T-cell leukemia. Since hybrids with the 10q+ chromosome also retained the human terminal deoxynucleotidyltransferase gene, it is further concluded that the terminal deoxynucleotidyltransferase locus is proximal to the TCL3 gene, at band 10q23-q24.
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PMID:Alpha-chain locus of the T-cell antigen receptor is involved in the t(10;14) chromosome translocation of T-cell acute lymphocytic leukemia. 288 38

The HOX11 homeobox gene was identified via the translocation t(10;14) in T cell leukaemia. To determine the function of this gene in mice, null mutations were made using homologous recombination in ES cells to incorporate lacZ into the hox11 transcription unit. Production of beta-galactosidase from the recombinant hox11 allele in +/- mutants allowed identification of sites of hox11 expression which included the developing spleen. Newborn hox11 -/- mice exhibit asplenia. Spleen formation commences normally at E11.5 in hox11 -/- mutant embryos but the spleen anlage undergoes rapid and complete resorption between E12.5 and E13.5. Dying spleen cells exhibit molecular features of apoptosis, suggesting that programmed cell death is initiated at this stage of organ development in the absence of hox11 protein. Thus hox11 is not required to initiate spleen development but is essential for the survival of splenic precursors during organogenesis. This function for hox11 suggests that enhanced cell survival may result from the t(10;14) which activates HOX11 in T cell leukaemias, further strengthening the association between oncogene-induced cell survival and tumorigenesis.
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PMID:The Hox11 gene is essential for cell survival during spleen development. 755 17

We report a case of adult T-cell leukemia (ATL) with complex chromosome abnormalities including an inversion (10)(q11q24) in a 64-year-old man. Although some abnormalities of chromosome 10 have been seen in ATL and other lymphoid neoplasias, inv(10)(q11q24) has previously been reported only in a case of T-cell chronic lymphocytic leukemia. Recent studies have revealed a rearrangement of a novel homeobox-containing gene called TCL-3 or HOX11 on 10q24 in T-cell acute lymphoblastic leukemia with the specific chromosome translocation t(10;14)(q24;q11), and thus the significance of 10q24 aberrations in leukemogenesis is indicated. We suggest that, despite the rarity of this anomaly, inv(10) (q11q24) may be a new chromosome inversion related to T-cell neoplasia and that the 10q24 anomaly may be an important cytogenetic clue for the elucidation of the pathogenesis of some peripheral T-cell neoplasias.
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PMID:Inversion(10)(q11q24) in a case of adult T-cell leukemia. 762 17

We have previously cloned two mouse homeobox genes Tlx-1 (T-cell leukemia homeobox gene-1) and a related gene Tlx-2 based on their homology to human HOX11, a putative proto-oncogene involved in human T-cell leukemia. We have mapped Tlx-1 to mouse chromosome 19 and Tlx-2 to chromosome 6 by linkage analysis using an interspecific backcross (C57BL/6J x Mus spretus) F1 x M. spretus. The proposed gene orders and genetic distances for Tlx-1 and Tlx-2 are centromere 19-Lpc-1-(25.53 cM)-Pltr-4-(5.32 cM)-Tlx-1- (3.19 cM)-Ins-1-(7.45 cM)-Xmv-18, and centromere 6-Tcrb-(12.90 cM)-Mltr-3-(10.75 cM)-Tlx-2-(18.42 cM)-Xmv-6.
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PMID:Genetic mapping of two mouse homeobox genes Tlx-1 and Tlx-2 to murine chromosomes 19 and 6. 769 66

The HOX11/TCL3 homeobox gene was identified at the breakpoint region in pediatric T-cell acute lymphoblastic leukemia harboring 10q24 chromosomal translocations. We previously reported that primary murine bone marrow cells transduced ex vivo with a recombinant HOX11-containing retrovirus, MSCV-HOX11, gave rise to cell lines at high frequency having characteristics of early myeloid cells. Cell lines were also established from the bone marrow and spleen of transplant recipients sacrificed 5 months after engraftment with MSCV-HOX11-transduced bone marrow cells. These latter lines, which exhibited a more differentiated myelomonocytic phenotype, harbored proviruses encoding a smaller HOX11 protein. None of the mice that received HOX11-expressing bone marrow cells or myeloid cell lines developed leukemia during 6-month observation periods. Here, we report that two bone marrow transplant recipients eventually developed T-cell acute lymphoblastic leukemia-like malignancies at 7 and 12 months posttransplant, indicating that progression to a fully malignant state required additional mutations. One tumor synthesized full-length HOX11 whereas the other expressed the smaller version of the protein. The smaller HOX11 protein suffered a carboxyl-terminal truncation. We subsequently constructed MSCV-based retroviral vectors expressing deleted forms of HOX11 and identified an amino-terminal region that was dispensible for generation of myeloid cell lines having a similar phenotype as those induced by full-length HOX11. We thus conclude that regions near the amino and carboxyl termini of HOX11 are not essential for transforming function, nor do they appear to determine the lineage or stage of differentiation of the target cell for transformation.
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PMID:Transforming function of the HOX11/TCL3 homeobox gene. 900 May 79

Hox11 is an orphan homeobox gene that controls the genesis of the spleen. HOX11 is also oncogenic, having been isolated from a chromosomal breakpoint in human T-cell leukaemia. Transgenic mice that redirected HOX11 to the thymus demonstrated cell-cycle aberration and progression to malignancy. We observed that the protein HOX11 interacted with protein serine-threonine phosphatase 2A catalytic subunit (PP2AC), as well as protein phosphatase 1 (PP1C) in mammalian cells. Inhibition of PP2A can regulate the cell cycle and control the activation of maturation-promoting factor in Xenopus oocytes. Microinjection of HOX11 into Xenopus oocytes arrested at the G2 phase of the cell cycle promoted progression to the M phase. G2 arrest can be induced by gamma-irradiation, but is eliminated by expression of HOX11 within a T-cell line. Thus HOX11 is a cellular oncogene that targets PP2A and PP1, both of which are targets for oncogenic viruses and chemical tumour promoters. This interaction suggests a mechanism by which a homeobox can alter the cell cycle.
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PMID:HOX11 interacts with protein phosphatases PP2A and PP1 and disrupts a G2/M cell-cycle checkpoint. 900 95

The HOX11 homeobox gene was first identified through studies of the t(7;10) and t(10;14) chromosomal translocations of acute T-cell leukemia. In addition, analysis of Hox11-/- mice has demonstrated a critical role for this gene in murine spleen development. A possible mode of in vivo function for the HOX11 protein in these two situations is regulation of target genes following DNA binding via the homeodomain, but little is known about how HOX11 regulates transcription in vivo. By performing transcriptional studies in yeast and mammalian one-hybrid systems, a modular transcriptional transactivation region at the NH2 terminus of HOX11 has been functionally dissected from other parts of the protein. This NH2-terminal region includes the previously identified short conserved Hep motif, which itself activates transcription in one-hybrid assays. The importance of the NH2-terminal region for the function of HOX11 in vivo was assayed by activating a HOX11-dependent gene in NIH 3T3 cells. Activation of this gene was found to be dependent upon an intact homeodomain in HOX11, but maximal activation was obtained only when the NH2-terminal 50 amino acids of HOX11 was present, showing that this region of HOX11 is important for in vivo transcriptional control of a chromosomal target gene.
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PMID:Optimal activation of an endogenous gene by HOX11 requires the NH2-terminal 50 amino acids. 958 90

Recent evidence suggests that in vertebrates the formation of distinct neuronal cell types is controlled by specific families of homeodomain transcription factors. Furthermore, the expression domains of a number of these genes correlates with functionally integrated neuronal populations. We have isolated two members of the divergent T-cell leukemia translocation (HOX11/Tlx) homeobox gene family from chick, Tlx-1 and Tlx-3, and show that they are expressed in differentiating neurons of both the peripheral and central nervous systems. In the peripheral nervous system, Tlx-1 and Tlx-3 are expressed in overlapping domains within the placodally derived components of a number of cranial sensory ganglia. Tlx-3, unlike Tlx-1, is also expressed in neural crest-derived dorsal root and sympathetic ganglia. In the CNS, both genes are expressed in longitudinal columns of neurons at specific dorsoventral levels of the hindbrain. Each column has distinct anterior and/or posterior limits that respect inter-rhombomeric boundaries. Tlx-3 is also expressed in D2 and D3 neurons of the spinal cord. Tlx-1 and Tlx-3 expression patterns within the peripheral and central nervous systems suggest that Tlx proteins may be involved not only in the differentiation and/or survival of specific neuronal populations but also in the establishment of neuronal circuitry. Furthermore, by analogy with the LIM genes, Tlx family members potentially define sensory columns early within the developing hindbrain in a combinatorial manner.
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PMID:Tlx-1 and Tlx-3 homeobox gene expression in cranial sensory ganglia and hindbrain of the chick embryo: markers of patterned connectivity. 965 Dec 21


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