Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:Q06643 (non-Hodgkin's lymphoma)
 11,307 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The chromosomal translocation t(11;14)(q13;q32) is observed in a number of lymphoid malignancies but is specifically associated with a particular subtype of non-Hodgkin's lymphoma called mantle cell lymphoma, where it is observed in up to 70% of cases. This translocation juxtaposes IGH sequences at 14q32 to a region variously termed BCL1/PRAD1 at 11q13, on the derivative chromosome 11. Detailed molecular analysis identified BCL1 to be a gene coding for the G1 cyclin, cyclin D1, which is an important regulator of the G1/S transition of the cell cycle. Cyclin D1 overexpression is observed in a vast majority of mantle cell lymphoma and lymphoid malignancies with 11q13 rearrangement, thereby confirming BCL1, now referred to as CCND1, as the gene targeted by these rearrangements. In this review, following a brief discussion of the role of cyclin D1 in cell cycle regulation, we discuss the mechanisms and pathogenetic impact of cyclin D1 activation in lymphoproliferative disorders with 11q13 rearrangement. We also review a number of the diagnostic strategies available for detection of CCND1 rearrangement/overexpression, with particular emphasis on applications for mantle cell lymphoma.
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PMID:Implication of cyclin D1 in malignant lymphoma. 925 2

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

Mutations and epigenetic alterations are key events in transforming normal cells to cancer cells. Mantle cell lymphoma (MCL), a non-Hodgkin's lymphoma of the B-cell, is an aggressive malignancy with poor prognosis especially for those patients who are resistant to the frontline drugs. There is a great need to describe the molecular basis and mechanism of drug resistance in MCL to develop new strategies for treatment. We reviewed frequent somatic mutations and mutations involving the B-cell pathways in MCL and discussed clinical trials that attempted to disrupt these gene pathways and/or epigenetic events. Recurrent gene mutations were discussed in the light of prognostic and therapeutic opportunity and also the challenges of targeting these lesions. Mutations in the ATM, CCND1, TP53, MLL2, TRAF2 and NOTCH1 were most frequently encountered in mantle cell lymphoma. Translational models should be built that would assess mutations longitudinally to identify important compensatory, pro-survival and anti-apoptic pathways and actionable genetic targets.
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PMID:Gene mutations and actionable genetic lesions in mantle cell lymphoma. 2744 94

Immunoglobulin heavy chain (IgH) translocations are common and early oncogenic events in B cell and plasma cell malignancies including B cell non-Hodgkin's lymphoma (NHL) and multiple myeloma (MM). IgH translocations bring oncogenes into close proximity with potent enhancer elements within the IgH locus, leading to oncogene up-regulation. As IgH enhancer activity is tightly controlled by B cell lineage-specific signaling and transcriptional networks, we hypothesized that IgH enhancers are potentially druggable targets/elements. To test this, we developed a molecular imaging-based high-throughput screening platform for discovering inhibitors of IgH enhancer-driven transcriptional activity. As proof of concept, we identified a low micromolar potency molecule (compound 30666) that inhibited immunoglobulin production by MM cells and blocked expression of an array of IgH translocation-induced oncogenes (CCND1, FGFR3/MMSET, and MYC) in MM and NHL cell lines. Prolonged exposure to 30666 significantly reduced the viability of IgH translocation-positive NHL and MM cells, but was less effective against cells lacking IgH translocations. Compound 30666 exhibited suitable pharmacological properties, including metabolic stability in liver microsomes and oral bioavailability in mice, and demonstrated preclinical anti-MM activity in a plasmacytoma mouse model. Our work suggests that IgH enhancers are attractive and potentially druggable targets for IgH translocation driven malignancies.
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PMID:Discovery platform for inhibitors of IgH gene enhancer activity. 3048 Nov 17