Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0598766 (leukemogenesis)
 4,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The t(10;14) chromosomal translocation of T-cell acute lymphoblastic leukemia joins the T-cell receptor delta gene to a region upstream of a diverged homeobox-containing gene called HOX11. To better understand the pathogenetic role of HOX11 in leukemogenesis, post 5-fluorouracil-treated murine bone marrow cells were infected with a replication-defective retrovirus bearing the gene. Constitutive expression of HOX11 in hematopoietic precursors yielded cell lines at high frequency consisting of immature cells belonging to the myeloid lineage. HOX11-transformed cell lines displayed a strict dependence on IL-3 for their survival and proliferation in culture and were not leukemogenic. The results support the hypothesis that the transforming capacity of HOX11 derives from its ability to alter the expression of genes regulating hematopoietic differentiation and that secondary mutations promoting cell survival or stimulating proliferation are required for progression to malignancy. The findings further suggest that the oncogenic activity of HOX11 might not be restricted to T-cell leukemias in humans.
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PMID:The HOX11 homeobox-containing gene of human leukemia immortalizes murine hematopoietic precursors. 790 17

HOX11 is identified from the breakpoint of human T cell acute lymphoblastic leukemias with t(10;14). Since overexpression of HOX11 in T cells caused leukemias in transgenic mice, the endogenous HOX11 may play a role in proliferation and differentiation of T cells. In order to elucidate the role, we examined the expression of Hox11 in normal lymphocytes by a reverse transcriptase-polymerase chain reaction analysis. Two alternatively spliced Hox11 mRNAs were expressed in fetal spleens. However, lymphocytes did not express Hox11 mRNA during differentiation. Furthermore, it was not induced in primary lymphocytes after activation. These results suggest that ectopic expression of HOX11 in T cells is responsible for leukemogenesis.
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PMID:Two forms of Hox11 a T cell leukemia oncogene, are expressed in fetal spleen but not in primary lymphocytes. 855 42

HOX11 is a homeodomain-containing oncogenic transcription factor that immortalizes hematopoietic precursor cells. The mechanism by which HOX11 facilitates this initial step of leukemogenesis is, however, not well understood. We have used a DNA binding site selection assay to investigate cooperative DNA binding by HOX11 with other transcription factors. A consensus sequence was derived and identified as the binding site for the CCAAT-box-binding transcription factors (CTF). HOX11 was shown to interact in vitro and in vivo with CTF1. Retrovirus-mediated transduction of an antisense CTF1 cDNA dramatically reduced the proliferative capacity of HOX11-immortalized hematopoietic precursor cells. CTF1 is, therefore, the first HOX11 protein partner identified that plays an important role in hematopoietic precursor cell immortalization.
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PMID:HOX11 interacts with CTF1 and mediates hematopoietic precursor cell immortalization. 1032 73

The mammalian PBX and Meis proteins belong to the TALE (three-amino acid-loop-extension) superfamily of homeodomain-containing transcription factors. Members of both the PBX and Meis groups have been implicated in tumorigenesis and are known to cooperatively bind DNA with Class I (clustered) HOX homeoproteins. Here we show that PBX and Meis homeoproteins cooperatively bind the PBX-responsive sequence in vitro with the oncoprotein encoded by the non-clustered homeobox gene HOX11 activated by the t(10;14)(q24;q11) chromosomal translocation in T-cell acute lymphoblastic leukemia (T-ALL). An FPWME motif N-terminal to the homeodomain is required for interaction with PBX proteins, which appears to confer DNA-binding specificity to HOX11. PBX proteins are highly expressed in HOX11 immortalized/transformed hematopoietic cells; in particular, the 10q24 translocation-carrying T-ALL Sil and K3P lines were found to selectively express PBX2. Ectopic retroviral-directed overexpression of PBX2 in concert with HOX11 in NIH3T3 cells resulted in decreased contact inhibition of growth as evidenced by focus formation in confluent cell monolayers. The accumulated data are thus consistent with a role of TALE homeoproteins in HOX11-mediated leukemogenesis.
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PMID:TALE homeoproteins as HOX11-interacting partners in T-cell leukemia. 1134 5

Human T cell leukemias can arise from oncogenes activated by specific chromosomal translocations involving the T cell receptor genes. Here we show that five different T cell oncogenes (HOX11, TAL1, LYL1, LMO1, and LMO2) are often aberrantly expressed in the absence of chromosomal abnormalities. Using oligonucleotide microarrays, we identified several gene expression signatures that were indicative of leukemic arrest at specific stages of normal thymocyte development: LYL1+ signature (pro-T), HOX11+ (early cortical thymocyte), and TAL1+ (late cortical thymocyte). Hierarchical clustering analysis of gene expression signatures grouped samples according to their shared oncogenic pathways and identified HOX11L2 activation as a novel event in T cell leukemogenesis. These findings have clinical importance, since HOX11 activation is significantly associated with a favorable prognosis, while expression of TAL1, LYL1, or, surprisingly, HOX11L2 confers a much worse response to treatment. Our results illustrate the power of gene expression profiles to elucidate transformation pathways relevant to human leukemia.
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PMID:Gene expression signatures define novel oncogenic pathways in T cell acute lymphoblastic leukemia. 1208 66

HOX11 is a homeobox gene originally identified at a chromosomal breakpoint in T-cell acute lymphoblastic leukemia (T-ALL). It is one of the most frequently deregulated genes in T-ALL, although the precise role of HOX11 in leukemogenesis as well as in normal development remains obscure. To gain more insight into the functional role of HOX11, we utilized a microarray model system to characterize the gene expression network that it directs. Using one of our T-ALL cell lines that had been stably transfected to express HOX11 and high-density oligonucleotide HG-U95A arrays, we identified a large number of differentially expressed genes in response to the enforced expression of HOX11. We focused on examining genes found to be up-regulated according to the microarray analysis and selected three putative target genes, NFKB2, SMARCD3, and NR4A3, for further investigation. We could not only confirm the up-regulation of NR4A3 by an independent method in all clones expressing HOX11, but luciferase reporter assays demonstrated that the effect that HOX11 exerted on the proximal promoter of NR4A3 was dependent on the presence of an intact homeodomain, providing support for the idea that HOX11 manifests its regulatory function via its action as a transcription factor.
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PMID:A microarray model system identifies potential new target genes of the proto-oncogene HOX11. 1538 72

The importance of HOXA genes in T-cell acute lymphoblastic leukemia (T-ALL) has recently been recognized. We report a novel chromosomal translocation in a T-ALL patient that maps upstream of the HOXA13 gene and downstream of the BCL11B/CTIP2 locus. Analysis of HOXA gene transcription demonstrated massive expression of HOXA13, whereas the other HOXA genes were unaffected. A genomic rearrangement of the HOXA locus associated with exclusive expression of HOXA13 was observed in a second patient. This situation resembles chromosomal translocations activating genes of the TLX/HOX11 family in T-ALLs. To compare the leukemogenic properties of HOXA13 to that of TLX proteins, cohorts of lethally irradiated mice were transplanted with bone marrow transduced with a retroviral vector expressing TLX3 or HOXA13. Cells transduced with TLX3 or HOXA13 could not be detected in the peripheral blood of mice post-transplantation and none of the mice developed malignancies. Cotransduction of the HOX cofactor MEIS1 with TLX3 or HOXA13 did not alter this outcome. However, in a myeloid clonogenic assay HOXA13 and TLX3 extended the proliferation of progenitors similarly to what was observed for TLX1. Altogether, our results strongly suggest the absolute requirement for cooperative events in association with homeobox gene up-regulation to induce T-cell leukemogenesis.
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PMID:Transforming potential of the T-cell acute lymphoblastic leukemia-associated homeobox genes HOXA13, TLX1, and TLX3. 1680 19

To identify new cytogenetic abnormalities associated with leukemogenesis or disease outcome, T-cell acute lymphoblastic leukemia (T-ALL) patient samples were analyzed by means of the array-comparative genome hybridization technique (array-CGH). Here, we report the identification of a new recurrent and cryptic deletion on chromosome 11 (del(11)(p12p13)) in about 4% (6/138) of pediatric T-ALL patients. Detailed molecular-cytogenetic analysis revealed that this deletion activates the LMO2 oncogene in 4 of 6 del(11)(p12p13)-positive T-ALL patients, in the same manner as in patients with an LMO2 translocation (9/138). The LMO2 activation mechanism of this deletion is loss of a negative regulatory region upstream of LMO2, causing activation of the proximal LMO2 promoter. LMO2 rearrangements, including this del(11)(p12p13) and t(11;14) (p13;q11) or t(7;11)(q35;p13), were found in the absence of other recurrent cytogenetic abnormalities involving HOX11L2, HOX11, CALM-AF10, TAL1, MLL, or MYC. LMO2 abnormalities represent about 9% (13/138) of pediatric T-ALL cases and are more frequent in pediatric T-ALL than appreciated until now.
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PMID:The cryptic chromosomal deletion del(11)(p12p13) as a new activation mechanism of LMO2 in pediatric T-cell acute lymphoblastic leukemia. 1687 70

Aberrant expression of the TLX1/HOX11 proto-oncogene is associated with a significant subset of T-cell acute lymphoblastic leukemias (T-ALL). Yet the manner in which TLX1 contributes to oncogenesis is not fully understood. Since, typically, interactions of HOX and TALE homeodomain proteins are determinant of HOX function, and HOX/MEIS co-expression has been shown to accelerate some leukemias, we systematically examined whether TLX1 interacts with MEIS and PBX proteins. Here, we report that TLX1 and MEIS proteins both interact and are co-expressed in T-ALL, and suggest that co-operation between TLX1 and MEIS proteins may have a significant role in T-cell leukemogenesis.
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PMID:MEIS proteins as partners of the TLX1/HOX11 oncoprotein. 1955 79


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