Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Constitutive NOTCH signaling in lymphoid progenitors promotes the development of immature T-cell lymphoblastic neoplasms (T-ALLs). Although it is clear that Notch signaling can initiate leukemogenesis, it has not previously been established whether continued NOTCH signaling is required to maintain T-ALL growth. We demonstrate here that the blockade of Notch signaling at two independent steps suppresses the growth and survival of NOTCH1-transformed T-ALL cells. First, inhibitors of presenilin specifically induce growth suppression and apoptosis of a murine T-ALL cell line that requires presenilin-dependent proteolysis of the Notch receptor in order for its intracellular domain to translocate to the nucleus. Second, a 62-amino-acid peptide derived from a NOTCH coactivator, Mastermind-like-1 (MAML1), forms a transcriptionally inert nuclear complex with NOTCH1 and CSL and specifically inhibits the growth of both murine and human NOTCH1-transformed T-ALLs. These studies show that continued growth and survival of NOTCH1-transformed lymphoid cell lines require nuclear access and transcriptional coactivator recruitment by NOTCH1 and identify at least two steps in the Notch signaling pathway as potential targets for chemotherapeutic intervention.
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PMID:Growth suppression of pre-T acute lymphoblastic leukemia cells by inhibition of notch signaling. 1250 63

NOTCH1 is involved in the pathogenesis of T-acute lymphoblastic leukemia (T-ALL) carrying the very rare translocation t(7;9)(q34;q34.3). We analyzed the expression of genes belonging to NOTCH pathway, in acute leukemia primary samples and lymphoblastoid cell lines. NOTCH1 pathway activation represents a common feature of T-ALL when compared to acute myelogenous leukemia (AML) and B-cell precursor acute lymphoblastic leukemia. The contemporary expression of NOTCH1 and its ligands on cell surface contributes to high levels of pathway activity. AML primary samples show high levels of JAGGED1 expression despite the low NOTCH1 pathway activation, consistent with an autonomous JAGGED1 signaling in myeloid leukemogenesis.
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PMID:A wide role for NOTCH1 signaling in acute leukemia. 1569 71

We analyzed NOTCH1 gene mutation in 53 adults with mature T-cell leukemia/lymphoma: 21 patients with adult T-cell leukemia (ATL), 25 with T-cell non-Hodgkin's lymphoma (T-NHL), and 7 with T-cell prolymphocytic leukemia. We detected a nonsense mutation, C7249T (resulting in Q2417X, where X is a termination codon) in the PEST domain of NOTCH1 in an ATL patient and detected a 3-bp deletion (positions 7234-7236) that resulted in deletion of a proline codon at codon 2412 in the PEST domain of NOTCH1 in a patient with a T-NHL, peripheral T-cell lymphoma-unspecified (PTCL-u). We also analyzed the expression of NOTCH1 target genes (HES1, CCND1, and MYC), all of which were expressed in the sample of the PTCL-u patient with the NOTCH1 mutation, but found only MYC to be expressed in the sample from the ATL patient. These findings suggest that nonsense mutation in the PEST domain in the ATL case was associated with NOTCH1 signaling through a pathway different from that for T-cell acute lymphoblastic leukemia (T-ALL). Although NOTCH1 mutation occurs infrequently in mature T-cell leukemia/lymphoma, NOTCH1 may be involved in leukemogenesis associated with various forms of T-cell leukemia/lymphoma rather than only with T-ALL.
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PMID:Detection of NOTCH1 mutations in adult T-cell leukemia/lymphoma and peripheral T-cell lymphoma. 1748 57

Notch signaling is of crucial importance in normal T-cell development and Notch 1 is frequently mutated in T-cell acute lymphoblastic leukemias (T-ALL), leading to aberrantly high Notch signaling. In this report, we determine whether T-ALL mutations occur not only in Notch1 but also in the F-box protein hCdc4 (Sel-10, Ago, or Fbxw7), a negative regulator of Notch1. We show that the hCDC4 gene is mutated in leukemic cells from more than 30% of patients with pediatric T-ALL and derived cell lines. Most hCDC4 mutations found were missense substitutions at critical arginine residues (Arg(465), Arg(479), and Arg(505)) localized in the substrate-binding region of hCdc4. Cells inactivated for hCdc4 and T-ALL cells containing hCDC4 mutations exhibited an increased Notch1 protein half-life, consistent with the proposed role of hCdc4 in ubiquitin-dependent proteolysis of Notch1. Furthermore, restoration of wild-type but not mutant hCdc4 in HCT 116 hCDC4-negative cells led to an increased Notch1 ubiquitylation and decreased Notch1 signaling. These results show that hCdc4 mutations interfere with normal Notch1 regulation in vivo. Finally, we found that mutations in hCDC4 and NOTCH1 can occur in the same cancers and that patients carrying hCDC4 and/or NOTCH1 mutations have a favorable overall survival. Collectively, these data show that mutation of hCDC4 is a frequent event in T-ALL and suggest that hCDC4 mutations and gain-of-function mutations in NOTCH1 might synergize in contributing to the development of pediatric T-ALL leukemogenesis.
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PMID:The tumor suppressor gene hCDC4 is frequently mutated in human T-cell acute lymphoblastic leukemia with functional consequences for Notch signaling. 1757 25

The acquired activation of stem cell leukemia (SCL) during T lymphopoiesis is a common event in T-cell acute lymphoblastic leukemia (T-ALL). Here, we generated tamoxifen (TAM)-inducible transgenic mice (lck-ER(T2)-SCL) to study the consequences of acquired SCL activation during T-cell development. Aberrant activation of SCL in thymocytes resulted in the accumulation of immature CD4(+)CD8(+) (double-positive, DP) cells by preventing normal surface expression of the T-cell receptor alphabeta (TCRalphabeta) complex. SCL-induced immature DP cells were further characterized by up-regulated NOTCH1 and generated noncycling polyclonal CD8(+)TCRbeta(low) cells. The prevalence of these cells was SCL dependent because TAM withdrawal resulted in their disappearance. Furthermore, we observed that SCL activation led to a dramatic up-regulation of NOTCH1 target genes (Hes-1, Deltex1, and CD25) in thymocytes. Strikingly, NOTCH1 target gene up-regulation was already observed after short-term SCL induction, implying that enhanced NOTCH signaling is mediated by SCL and is not dependent on secondary genetic events. These data represent the basis for a novel pathway of SCL-induced leukemogenesis and provide a functional link between SCL and NOTCH1 during this process.
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PMID:NOTCH1 pathway activation is an early hallmark of SCL T leukemogenesis. 1769 35

X-linked SCID (SCID-X1) is amenable to correction by gene therapy using conventional gammaretroviral vectors. Here, we describe the occurrence of clonal T cell acute lymphoblastic leukemia (T-ALL) promoted by insertional mutagenesis in a completed gene therapy trial of 10 SCID-X1 patients. Integration of the vector in an antisense orientation 35 kb upstream of the protooncogene LIM domain only 2 (LMO2) caused overexpression of LMO2 in the leukemic clone. However, leukemogenesis was likely precipitated by the acquisition of other genetic abnormalities unrelated to vector insertion, including a gain-of-function mutation in NOTCH1, deletion of the tumor suppressor gene locus cyclin-dependent kinase 2A (CDKN2A), and translocation of the TCR-beta region to the STIL-TAL1 locus. These findings highlight a general toxicity of endogenous gammaretroviral enhancer elements and also identify a combinatorial process during leukemic evolution that will be important for risk stratification and for future protocol design.
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PMID:Insertional mutagenesis combined with acquired somatic mutations causes leukemogenesis following gene therapy of SCID-X1 patients. 1868 86

To identify dysregulated pathways in distinct phases of NOTCH1-mediated T-cell leukemogenesis, as well as small-molecule inhibitors that could synergize with or substitute for gamma-secretase inhibitors (GSIs) in T-cell acute lymphoblastic leukemia (T-ALL) therapy, we compared gene expression profiles in a Notch1-induced mouse model of T-ALL with those in human T-ALL. The overall patterns of NOTCH1-mediated gene expression in human and mouse T-ALLs were remarkably similar, as defined early in transformation in the mouse by the regulation of MYC and its target genes and activation of nuclear factor-kappaB and PI3K/AKT pathways. Later events in murine Notch1-mediated leukemogenesis included down-regulation of genes encoding tumor suppressors and negative cell cycle regulators. Gene set enrichment analysis and connectivity map algorithm predicted that small-molecule inhibitors, including heat-shock protein 90, histone deacetylase, PI3K/AKT, and proteasome inhibitors, could reverse the gene expression changes induced by NOTCH1. When tested in vitro, histone deacetylase, PI3K and proteasome inhibitors synergized with GSI in suppressing T-ALL cell growth in GSI-sensitive cells. Interestingly, alvespimycin, a potent inhibitor of the heat-shock protein 90 molecular chaperone, markedly inhibited the growth of both GSI-sensitive and -resistant T-ALL cells, suggesting that its loss disrupts signal transduction pathways crucial for the growth and survival of T-ALL cells.
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PMID:Interconnecting molecular pathways in the pathogenesis and drug sensitivity of T-cell acute lymphoblastic leukemia. 2000 43

A 6-year-old Japanese female was diagnosed as having myeloid/NK cell precursor acute leukemia (MNKL) using immunocytochemical analysis. The patient was treated by cord blood transplantation from an HLA 1-locus mismatched unrelated donor after chemotherapy comprising cytosine arabinoside, idarubicin, etoposide, and L-asparaginase. We detected a nonsense mutation, C7412A, resulting in S2471X, where X is a terminal codon, in the PEST domain of NOTCH1 in this patient. The presence of the NOTCH1 activating mutation in MNKL might suggest a possible role in the leukemogenesis of MNKL.
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PMID:NOTCH1 mutation in a female with myeloid/NK cell precursor acute leukemia. 2073 Aug 82

Ras guanyl nucleotide-releasing proteins (RasGRPs) are activators of Ras. Previous studies have indicated the possible involvement of RasGRP1 and RasGRP4 in leukemogenesis. Here, the predominant role of RasGRP1 in T-cell leukemogenesis is clarified. Notably, increased expression of RasGRP1, but not RasGRP4, was frequently observed in human T-cell malignancies. In a mouse bone marrow transplantation model, RasGRP1 exclusively induced T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) after a shorter latency when compared with RasGRP4. Accordingly, Ba/F3 cells transduced with RasGRP1 survived longer under growth factor withdrawal or phorbol ester stimulation than those transduced with RasGRP4, presumably due to the efficient activation of Ras. Intriguingly, NOTCH1 mutations resulting in a gain of function were found in 77% of the RasGRP1-mediated mouse T-ALL samples. In addition, gain-of-function NOTCH1 mutation was found in human T-cell malignancy with elevated expression of RasGRP1. Importantly, RasGRP1 and NOTCH1 signaling cooperated in the progression of T-ALL in the murine model. The leukemogenic advantage of RasGRP1 over RasGRP4 was attenuated by the disruption of a protein kinase C phosphorylation site (RasGRP1(Thr184)) not present on RasGRP4. In conclusion, cooperation between aberrant expression of RasGRP1, a strong activator of Ras, and secondary gain-of-function mutations of NOTCH1 have an important role in T-cell leukemogenesis.
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PMID:Aberrant expression of RasGRP1 cooperates with gain-of-function NOTCH1 mutations in T-cell leukemogenesis. 2211 51

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world and shows a remarkable heterogeneity in the clinical course. Understand the genetic basis of CLL may help in clarifying the molecular bases of this clinical heterogeneity. Recurrent chromosomal aberrations at 13q14, 12q, 11q22-q23 and 17p13, and TP53 mutations are the first genetic lesions identified as drivers of the disease. While some of these lesions are associated with poor outcome (17p13 deletion, TP53 mutations and, to a lesser extent, 11q22-q23 deletion) others are linked to a favorable course (13q14 deletion as sole aberration). Recently, next generation sequencing has revealed additional recurrent alterations in CLL targeting the NOTCH1, SF3B1, and BIRC3 genes. NOTCH1, SF3B1, and BIRC3 lesions provide: I) new insights on the mechanisms of leukemogenesis, tumor progression and chemoresistance in this leukemia; II) new biomarkers for the identification of poor risk patients, having individually shown correlations with survival in CLL; and III) new therapeutic targets, especially in the setting of high risk disease. This review will summarize the most important genetic aberrations in CLL and how our improved knowledge of the genome of leukemic cells may translate into improved patients' management.
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PMID:The spectrum of genetic defects in chronic lymphocytic leukemia. 2320 64


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