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Query: UMLS:C0023418 (leukemia)
 93,477 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Non-random translocation involving the short arm of chromosome 19 are frequently observed in acute leukemias. Recent studies have shown that the 19p13 genes E2A and LYLl, both of which encode helix-loop-helix proteins, lie at two different translocation breakpoints in acute lymphoblastic leukemias (ALL). The E2A gene is involved by the t(1;19)(q23;p13) in acute pre-B-cell leukemias and the LYL1 gene is structurally altered by a t(7;19)(q34;p13) in T-cell ALL. To assess the role of these genes in other leukemia-associated translocations we mapped their locations with respect to the t(11;19)(q23;p13) and t(4;19)(q21;p13) translocation breakpoints carried by T-ALL cell lines SUP-T13 and SUP-T8a, respectively. In situ hybridization studies indicated that the E2A and LYL1 genes are physically distinct from the t(4;19) and t(11;19) breakpoints. Using these and other 19p13 translocation breakpoints as landmarks, we established a partial physical map of 19p: 19pter-E2A-INSR-LYL1-[t(4;19)]-19cen. These data should help guide molecular studies to further characterize 19p13 breakpoints and mapping of genes in this chromosomal region.
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PMID:Mapping of translocation breakpoints on the short arm of chromosome 19 in acute leukemias by in situ hybridization. 226 76

The protein products of proto-oncogenes implicated in T cell acute lymphoblastic leukemia include two distinct families of presumptive transcription factors. RBTN1 and RBTN2 encode highly related proteins that possess cysteine-rich LIM motifs. TAL1, TAL2 and LYL1 encode a unique subgroup of basic helix-loop-helix (bHLH) proteins that share exceptional homology in their bHLH sequences. We have found that RBTN1 and RBTN2 have the ability to interact with each of the leukemogenic bHLH proteins (TAL1, TAL2 and LYL1). These interactions occur in vivo and appear to be mediated by sequences within the LIM and bHLH domains. The LIM-bHLH interactions are highly specific in that RBTN1 and RBTN2 will associate with TAL1, TAL2 and LYL1, but not with other bHLH proteins, including E12, E47, Id1, NHLH1, AP4, MAX, MYC and MyoD1. Moreover, RBTN1 and RBTN2 can interact with TAL1 polypeptides that exist in assembled bHLH heterodimers (e.g. TAL1-E47), suggesting that the RBTN proteins can influence the functional properties of TAL1. Finally, we have identified a subset of leukemia patients that harbor tumor-specific rearrangements of both their RBTN2 and TAL1 genes. Thus, the activated alleles of these genes may promote leukemia cooperatively, perhaps as a result of bHLH-LIM interactions between their protein products.
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PMID:Specific in vivo association between the bHLH and LIM proteins implicated in human T cell leukemia. 795 52

TAL1 gene rearrangement is the most common genetic defect associated with T cell acute lymphoblastic leukaemia (T-ALL). Tumour-specific rearrangements of TAL1 arise as a result of either chromosome translocation or local DNA recombination. TAL1 gene products possess the basic helix-loop-helix (bHLH) motif, a DNA-binding domain common to several known transcription factors. The bHLH domain of TAL1 is especially homologous to those encoded by TAL2 and LYL1, distinct genes that were also identified on the basis of chromosomal rearrangement in T-ALL. Thus, TAL1, TAL2 and LYL1 constitute a unique family of bHLH proteins, each of which is a potential mediator of T cell leukaemogenesis.
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PMID:TAL1, TAL2 and LYL1: a family of basic helix-loop-helix proteins implicated in T cell acute leukaemia. 814 19

We report on a patient with acute myeloid leukemia (AML M4) and a so far unrecorded translocation (17;19). The leukemia transformed from a myeloproliferative disorder (MPD) and showed a progressive fatal course. Following transformation, all leukemic cells showed an apparently balanced translocation (17;19)(p13;p13). The breakpoint regions harbor genes such as TP53 (17p13) and E2A, ENL, or LYL1 (19p13), which could be relevant in leukemogenesis. We suspect that the translocation (17;19)(p13;p13) may be a prognostic factor for transformation from chronic MPD to acute leukemia.
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PMID:A novel translocation (17;19)(p13;p13) in a patient with acute myelomonocytic leukemia. 1081 77

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

T-cell acute lymphoblastic leukemia (T-ALL) presents a difficult medical problem. T-ALL's clinical features and the biological properties of the leukemia cells are not predictive of prognosis, and thus have not been useful for risk-specific adjustments in therapeutic intensity. Microarray gene expression analyses of T-cell leukemic lymphoblasts have not only improved our understanding of the biological heterogeneity of this disease but have revealed clinically relevant molecular subtypes. Five different multistep molecular pathways have been identified that lead to T-ALL, involving activation of different T-ALL oncogenes: (1) HOX11, (2) HOX11L2, (3) TAL1 plus LMO1/2, (4) LYL1 plus LMO2, and (5) MLL-ENL. Gene expression studies indicate activation of a subset of these genes-HOX11, TAL1, LYL1, LMO1, and LMO2-in a much larger fraction of T-ALL cases than those harboring activating chromosomal translocations. In many such cases, the abnormal expression of one or more of these oncogenes is biallelic, implicating upstream regulatory mechanisms. Among these molecular subtypes, overexpression of the HOX11 orphan homeobox gene occurs in approximately 5% to 10% of childhood and 30% of adult T-ALL cases. Patients with HOX11-positive lymphoblasts have an excellent prognosis when treated with modern combination chemotherapy, while cases at high risk of early failure are included largely in the TAL1- and LYL1-positive groups. Supervised learning approaches applied to microarray data have identified a group of genes whose expression is able to distinguish high-risk cases. Further analyses of gene expression signatures of T-ALL lymphoblasts are especially needed for patients treated on modern combination chemotherapy trials to clearly distinguish the 10% to 15% of patients who fail induction or relapse in the first year of treatment. These high-risk patients would be ideal candidates for more intensive therapies in first remission, such as myeloablative regimens with stem cell rescue. Based on the rapid pace of research in T-ALL, made possible in large part through microarray technology, deep analysis of molecular pathways should lead to new and much more specific targeted therapies.
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PMID:Gene expression profiling in T-cell acute lymphoblastic leukemia. 1458 78

The activation of oncogenic transcription factors defines distinct molecular subsets of T-cell acute lymphoblastic leukaemia and has prognostic relevance in children. We investigated the prognostic effect of the expression levels of eight oncogenic transcription factors--TLX1 (HOX11), TLX3 (HOX11L2), TAL1, TAL2, LYL1, OLIG2 (BHLHB1), LMO1, and LMO2--in 52 adults with T-cell acute lymphoblastic leukaemia. The leukaemia-specific survival rate for the 16 TLX1-positive patients was 88% (90% CI 73-100%), compared with 56% (42-70%) for all other cases (p=0.019). Only the TLX1 oncogene expression subgroup showed difference in leukaemia-specific survival. Our results suggest that overexpression of TLX1 confers a good outlook for adults with T-cell acute lymphoblastic leukaemia. Furthermore, our findings lead to questions about whether stem-cell transplantation in first remission is necessary for effective treatment of patients in the low-risk subgroup of patients with TLX1 oncogene expression.
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PMID:Prognostic importance of TLX1 (HOX11) oncogene expression in adults with T-cell acute lymphoblastic leukaemia. 1497 18

The LYL1 gene encodes a basic helix-loop-helix transcription factor involved in T-cell acute lymphoblastic leukemia. Using real-time quantitative RT-PCR assay, we found that the expression of LYL1 was at higher levels in the majority cases of acute myeloblastic leukemia (AML) or myelodysplastic syndrome when compared to normal bone marrow. Our study also showed that LYL1 was highly expressed in most AML cell lines and in CD34+ AML cells. To determine whether LYL1 had an affect on the phenotype and behavior of myeloid cells, we introduced full-length LYL1 cDNA into K562 cells using electroporation and U937 cells with retroviral infection. Both of the derivative cell lines with overexpression of LYL1 had an increased growth rate and clonogenecity. Forced expression of LYL1 in K562 cells enhanced spontaneous and hemin-induced erythroid differentiation but blocked spontaneous as well as PMA-induced megakaryocytic differentiation. Overexpression of LYL1 in U937 cells blocked all-trans retinoic acid-induced monocytic differentiation. The LYL1-transfected U937 cells were also more resistant to the cytotoxic drug cytarabine. These results demonstrate that LYL1 may play a role in early hematopoiesis and may be a potential oncogenic factor in AML.
Leukemia 2005 Nov
PMID:Oncogenic potential of the transcription factor LYL1 in acute myeloblastic leukemia. 1609 22

The occurrence of leukemia in a gene therapy trial for SCID-X1 has highlighted insertional mutagenesis as an adverse effect. Although retroviral integration near the T-cell acute lymphoblastic leukemia (T-ALL) oncogene LIM-only protein 2 (LMO2) appears to be a common event, it is unclear why LMO2 was preferentially targeted. We show that of classical T-ALL oncogenes, LMO2 is most highly transcribed in CD34+ progenitor cells. Upon stimulation with growth factors typically used in gene therapy protocols transcription of LMO2, LYL1, TAL1 and TAN1 is most prominent. Therefore, these oncogenes may be susceptible to viral integration. The interleukin-2 receptor gamma chain (IL2Rgamma), which is mutated in SCID-X1, has been proposed as a cooperating oncogene to LMO2. However, we found that overexpressing IL2Rgamma had no effect on T-cell development. In contrast, retroviral overexpression of LMO2 in CD34+ cells caused severe abnormalities in T-cell development, but B-cell and myeloid development remained unaffected. Our data help explain why LMO2 was preferentially targeted over many of the other known T-ALL oncogenes. Furthermore, during T-cell development retrovirus-mediated expression of IL2Rgamma may not be directly oncogenic. Instead, restoration of normal IL7-receptor signaling may allow progression of T-cell development to stages where ectopic LMO2 expression causes aberrant thymocyte growth.
Leukemia 2007 Apr
PMID:Ectopic retroviral expression of LMO2, but not IL2Rgamma, blocks human T-cell development from CD34+ cells: implications for leukemogenesis in gene therapy. 1726 20

The Ets-related gene (ERG) is an Ets-transcription factor required for normal blood stem cell development. ERG expression is down-regulated during early T-lymphopoiesis but maintained in T-acute lymphoblastic leukemia (T-ALL), where it is recognized as an independent risk factor for adverse outcome. However, it is unclear whether ERG is directly involved in the pathogenesis of T-ALL and how its expression is regulated. Here we demonstrate that transgenic expression of ERG causes T-ALL in mice and that its knockdown reduces the proliferation of human MOLT4 T-ALL cells. We further demonstrate that ERG expression in primary human T-ALL cells is mediated by the binding of other T-cell oncogenes SCL/TAL1, LMO2, and LYL1 in concert with ERG, FLI1, and GATA3 to the ERG +85 enhancer. This enhancer is not active in normal T cells but in transgenic mice targets expression to fetal liver c-kit(+) cells, adult bone marrow stem/progenitors and early CD4(-)CD8(-) double-negative thymic progenitors. Taken together, these data illustrate that ERG promotes T-ALL and that failure to extinguish activity of stem cell enhancers associated with regulatory transcription factors such as ERG can contribute to the development of leukemia.
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PMID:ERG promotes T-acute lymphoblastic leukemia and is transcriptionally regulated in leukemic cells by a stem cell enhancer. 2153 59


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