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Actuation of NOTCH1 by Leukemia-Associated Mutations. Malecki et al, Mol Cell Biol 2006; ... NF-B ctivation is not adequate for T-cell leukemia in the nonappearance ...
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Score: an Introduction Notch receptors take an interest in a moderated flagging pathway that controls various cell separation programs in metazoans Genetic investigations have clarified differing CONTEXT-ward and DOSE-subordinate capacities for Notch flagging These different capacities are interceded through a sign transduction pathway depending on the managed proteolysis of Notch receptors

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Notch Structure and Activation Cleavage at site S1 amid receptor development makes two non-covalently related subunits shielded from untimely actuation by NRR and the HD. Ligand restricting impels a cleavage at site S2 by ADAM-sort metallo-protease took after by an extra cleavage at site S3 by  - secretase.

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Notch-Induced Signaling

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In mice, Notch1 has a non-repetitive part amid the soonest phases of T-cell advancement, including beginning duty to T-cell destiny and ensuing movement to the DN3 phase of improvement There is a flat out prerequisite for Notch for T-cell ancestors of the  genealogy to advance past the DN3  determination checkpoint

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NOTCH Function in Normal Thymopoiesis Maillard et al , Annu Rev Immunol 2005; 23:945-974

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NOTCH Function in Normal Thymopoiesis Small atom inhibitors of  - secretase, contingent knockout of CSL , or overwhelming negative types of genius like-1 (MAML) reiterate the phenotypes saw with loss of Notch1 capacity, ensnaring the sanctioned flagging pathway and the CSL/ICN/Mastermind complex in thymic advancement

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Discovery of Oncogenic NOTCH Alleles Human NOTCH1 was distinguished through its inclusion by a repeating chromosomal translocation t(7;9)(q34;q34.3) in a phone line (SUPT-1) got from a patient with T-ALL In these breakpoints, DNA groupings 3\' of the breakpoints are combined to TCR  promoter/enhancer arrangements, bringing about combination of a progression of N-terminally truncated (and constitutively actuated) NOTCH1 polypeptides SUPT-1 cells were development repressed by prevailing negative MAML1 yet not by GSIs, demonstrating that some t(7;9)- particular NOTCH1 proteins get to the core in a  - secretase-autonomous style Although intermittent, this translocation is seen in <1% of patients with T-ALL Ellisen et al , Cell 1991; 66:649-661

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Discovery of Oncogenic NOTCH Alleles In 2004, Aster, Look, and partners found two sorts of enacting transformations in NOTCH1 , no less than one of which is found in ~55-60% of human T-ALLs, making it the most regular hereditary modification in this type of leukemia This occurred through testing of T-ALL phone lines without the t(7;9) for their affectability (NOTCH reliance) to a  - secretase Inhibitor Sequencing uncovered NOTCH1 changes in cell lines that were touchy and numerous that were heartless to the GSI Sequencing likewise indicated HD (both HD-N and HD-C) and PEST space transformations in a progression of essential T-ALL examples from 96 youngsters at conclusion Importantly, NOTCH1 changes were found in relationship with oncogenes of all the major sub-atomic subtypes of T-ALL, proposing it can possibly impact different flagging pathways Weng et al , Science 2004; 306:269-271

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Discovery of Oncogenic NOTCH Alleles Sequencing uncovered transformations including both the HD-N (missense) and PEST areas (insertions/erasures) Weng et al , Science 2004; 306:269-271

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Discovery of Oncogenic NOTCH Alleles Western smudge examination uncovered that phone lines with HD-N and PEST space changes contained a polypeptide of expected size for NTM, in addition to extra (littler) polypeptides Weng et al , Science 2004; 306:269-271

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Discovery of Oncogenic NOTCH Alleles Using a NOTCH-delicate journalist, HD-N changes brought about a 3-to 9-fold increment in luciferase action and PEST area changes a ~1.5-to 2-fold increment When HD and PEST space changes were available in cis , 20-to 40-fold increments were measured Weng et al , Science 2004; 306:269-271

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Activation of NOTCH1 by Leukemia-Associated Mutations Schematic representation of human NOTCH1 receptor with the leukemia-related changes concentrated on Malecki et al , Mol Cell Biol 2006; 26:4642-4651

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Activation of NOTCH1 by Leukemia-Associated Mutations HD space changes brought about initiation of NOTCH1 motioning with regards to both full-length NOTCH1 (An) and ligand restricting faulty  EGF NOTCH1 (B) Malecki et al , Mol Cell Biol 2006; 26:4642-4651

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Activation of NOTCH1 by Leukemia-Associated Mutations GSI treatment repealed the stimulatory impact of HD transformations in full-length NOTCH1 (An) and these changes created expanded S2 and S3 cleavage Malecki et al , Mol Cell Biol 2006; 26:4642-4651

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Activation of NOTCH1 by Leukemia-Associated Mutations Classification of leukemia-related HD transformations Class I: separation or diminished solidness of heterodimer Class II: no impact on hetero-dimer soundness however a repositioning of S2 site far from defensive buildups Malecki et al , Mol Cell Biol 2006; 26:4642-4651

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Normal and Pathophysiologic NOTCH1 Signaling Biochemical and hereditary information recommend that PEST space changes increment Notch motioning by upgrading the STABILITY of the ICN, while changes in HD-N and HD-C are anticipated to upgrade PRODUCTION of the ICN by destabilizing intersubunit affiliation Pear and Aster, Curr Opin Hematol 2004; 11:426-433

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Incidence of NOTCH1 Mutations in T-ALL 71% 56% Mansour et al , Leukemia 2006; 20:537-539

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Distribution of genomic deviations and NOTCH1 transformations in pediatric T-ALL

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Prognostic Significance of NOTCH1 Mutations in T-ALL In an investigation of 77 licenses with T-ALL, 32 transformations recognized in 29 off 77 patients (38% rate) NOTCH1 change was more incessant in patients with high white numbers and was connected with shorter survival (both backslide free and general survival) The relationship amongst change and survival was noteworthy just in grown-up patients This negative impact on forecast was potentiated by a few oncogenes ( HOX11L2 ) and constricted by others ( HOX11 ) Zhu et al , Clin Cancer Res 2006; 12:3043-3049

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Prognostic Significance of NOTCH1 Mutations in T-ALL In an investigation of 157 pediatric patients with T-ALL treated consistently, NOTCH1 changes were found in 52%: 67% in HD, 16% in the PEST space, and 17% in both The nearness of transformation corresponded altogether with a superb early reaction to treatment (great prednisone reaction, positive MRD energy) Activating NOTCH1 transformations connected with better occasion free survival (lower rate of backslide than in patients with germline NOTCH ) This brings up issue of how molecularly focused on treatment can be best tried with regards to and/or coordinated into momentum treatment Breit et al , Blood 2006; 108:1151-1157

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Evidence for Oncogenic Activity of Activated Notch/NOTCH In Vivo Development of T-cell neoplasms in mice transplanted with bone marrow communicating enacted Notch/NOTCH alleles: Pear et al , J Exp Med 1996; 183:2283-2291 Development of T-cell neoplasms in mice bearing actuated Notch transgenes: Robey et al 1996; Cell 87:483-492. Advancement of T-cell neoplasms in zebrafish bearing an actuated NOTCH transgene: Chen et al , Leukemia 2007; 21:462-471

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Evidence for Oncogenic Activity of Activated Notch/NOTCH In Vivo It is likely that the tranforming activities of NOTCH mirror its ordinary parts in T-cell improvement, i.e. drive pluripotent bone marrow cells toward T-cell destiny and extend the pool of juvenile T cell ancestors NOTCH1 changes could happen in extremely youthful T ancestry cells or uncommitted pluripotent marrow forebears In this model, NOTCH1 changes are EARLY occasions that set the phase for procurement of other hereditary abnormalities

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Activating Notch1 Mutations are Frequent in Mouse Models of T-ALL Notch1 is often changed in murine models of T-ALL 68% of cell lines + 59% of tumors from TAL1/LMO1, OLIG2/LMO1, OLIG2, LMO1, NUP98/HOXD13, and p27 -/ -/SMAD3 +/ - mice (Lin et al , Blood 2006; 107:2540-2543) 74% of tumors from TAL1, TAL1/HEB +/ - , and TAL1/Ink4a/Arf +/ - mice and 31% of tumors from mice lacking for different blends of H2AX, p53, and Rag2 (O\'Neill et al , Blood 2006; 107:781-785) Mutations were seen in HD (most single-base substitutions) and in the PEST area (most insertions or cancellations) These were obtained moderately right on time during the time spent leukemic change Cell lines got from these tumors experienced G 0/G 1 capture and apoptosis when treated with a GSI

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Activating Notch1 Mutations are Frequent in Mouse Models of T-ALL The continuous relationship of Notch1 transformations with different oncogenes and the limit of actuated Notch1 alleles to participate with a few qualities in mouse models of T-AL are reminiscent of the relationship of NOTCH1 changes with numerous sub-atomic subtypes of human T-ALL There might be a particular, basic arrangement of NOTCH1-ward signals not effortlessly made generally or NOTCH1 might have the capacity to initiate various professional changing pathways at the same time

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Summary of Findings from Notch/NOTCH Transgene Studies T-cell harm was prompted with high penetrance and with a shorter idleness than saw with different oncogenes ( e.g. TAL1, LMO2) The immunophenotype of mouse tumors was like that in human leukemias with NOTCH initiation ( e.g. CD4 +/CD8 + twofold positive) Even when a promoter for the most part dynamic in hematopoietic cells was utilized, T-cell neoplasms grew only Mice doubly transgenic for enacted Notch and another T-cell oncogene ( e.g. myc ) created tumors with much shorter inertness than separately transgenic mice

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