vdj-seq-deep-sequencing-analysis-rearranged-immunoglobulin-heavy

VDJ-Seq: Deep Sequencing Analysis of Rearranged Immunoglobulin Heavy Chain Gene to Reveal Clonal Evolution Patterns of B Cell Lymphoma

Understanding tumor clonality is critical to understanding the mechanisms involved in tumorigenesis and disease progression. In addition, understanding ...

Weill Cornell Medical College

Significance of PRDM1beta expression as a prognostic marker in diffuse large B-cell lymphomas.

PRDM1/&#x98DE;&#x8247;-1&#xFF0C;&#x4E3B;&#x8C03;&#x8282;&#x5668;&#x5728;&#x7EC8;&#x7AEF;&#x7684; B &#x7EC6;&#x80DE;&#x5206;&#x5316;&#xFF0C;&#x6700;&#x8FD1;&#x5DF2;&#x4F5C;&#x4E3A;&#x6FC0;&#x6D3B; B &#x7EC6;&#x80DE;&#x7C7B;&#x578B;&#x7684;&#x5F25;&#x6F2B;&#x6027;&#x5927; B &#x7EC6;&#x80DE;&#x6DCB;&#x5DF4;&#x7624;&#x7A81;&#x53D8;&#x706D;&#x6D3B;&#x80BF;&#x7624;&#x6291;&#x764C;&#x7684;&#x76EE;&#x6807;&#x3002;&#x6211;&#x4EEC;&#x8FD9;&#x91CC;&#x7684;&#x7814;&#x7A76;&#x8868;&#x660E; PRDM1/&#x98DE;&#x8247;-1 &#x4E5F;&#x662F; microRNA (&#x7C73;&#x5C14;) &#x7684;&#x76EE;&#x6807;-&#x4ECB;&#x5BFC;&#x7684;&#x548C;&#x5E73;&#x53F7;&#x7A7A;&#x95F4;&#x7AD9; 9 &#x548C;&#x8BA9;-7a &#x970D;&#x5947;&#x91D1;/&#x91CC;&#x5FB7;-&#x65AF;&#x6ED5;&#x4F2F;&#x683C; (HRS) &#x7EC6;&#x80DE;&#x7684;&#x970D;&#x5947;&#x91D1;&#x6DCB;&#x5DF4;&#x7624; (HL) &#x4E0B;&#x8C03;&#x3002;&#x7C73;&#x5C14;&#x8868;&#x8FBE;&#x5F0F;&#x901A;&#x8FC7;&#x76F4;&#x63A5;&#x7C73;&#x5C14;&#x514B;&#x9686;&#x5206;&#x6790;&#x8868;&#x660E;&#x8FD9;&#x4E9B; Mirna &#x4E24;&#x8005;&#x4E4B;&#x95F4;&#x6700;&#x5927;&#x9AD8;&#x5EA6;&#x8868;&#x793A; HRS &#x7EC6;&#x80DE;&#x3002;&#x8FD9;&#x4E9B; Mirna &#x529F;&#x80FD;&#x9488;&#x5BF9;&#x7279;&#x5B9A;&#x7ED1;&#x5B9A;&#x7AD9;&#x70B9;&#x5728; PRDM1/&#x98DE;&#x8247;-1 mRNA 3&#39; &#x975E;&#x7FFB;&#x8BD1;&#x533A;&#x548C;&#x8367;&#x5149;&#x7D20;&#x9176;&#x8BB0;&#x8005;&#x6D3B;&#x52A8;&#x901A;&#x8FC7;&#x7FFB;&#x8BD1;&#x7684;&#x9547;&#x538B;&#x548C;&#x538B;&#x8FEB;&#x3002;&#x6B64;&#x5916;&#xFF0C;&#x9AD8;&#x6C34;&#x5E73;&#x7684;&#x548C;&#x5E73;&#x53F7;&#x7A7A;&#x95F4;&#x7AD9; 9 &#x548C;&#x8BA9;-7a &#x4E2D; HL &#x7EC6;&#x80DE;&#x4E0E;&#x4F4E;&#x6C34;&#x5E73;&#x7684; PRDM1/&#x98DE;&#x8247;-1 &#x76F8;&#x5173;&#x7684;&#x884C;&#x3002;&#x7C7B;&#x4F3C;&#x4E8E;&#x4F53;&#x5916;&#x540C;&#x884C; HRS &#x7EC6;&#x80DE;&#x4E3B;&#x8981; HL &#x4E8B;&#x4F8B;&#x8868;&#x660E;&#x5F31;&#x6216;&#x6CA1;&#x6709; PRDM1/&#x98DE;&#x8247;-1 &#x8868;&#x8FBE;&#x5F0F;&#x4E2D;&#x7684;&#x5927;&#x591A;&#x6570;&#x3002;&#x548C;&#x5E73;&#x53F7;&#x7A7A;&#x95F4;&#x7AD9; 9 &#x6216;&#x8BA9;-7a &#x7684;&#x8FC7;&#x91CF;&#x8868;&#x8FBE;&#x51CF;&#x5C11; U266 &#x7EC6;&#x80DE; PRDM1/&#x98DE;&#x8247;-1 &#x6C34;&#x5E73; 30%&#x81F3; 50%&#xFF0C;&#x800C;&#x540C;&#x65F6;&#x6291;&#x5236;&#x5176; L428 &#x7EC6;&#x80DE;&#x6D3B;&#x52A8;&#x5BFC;&#x81F4;&#x5927;&#x7EA6; 2.6-fold &#x8BF1;&#x5BFC;&#x7684; PRDM1/&#x98DE;&#x8247;-1&#x3002;PRDM1/&#x98DE;&#x8247;-1 &#x4ECB;&#x5BFC;&#x7C73;&#x5C14;&#x4E0B;&#x8C03;&#x53EF;&#x80FD;&#x5E72;&#x6270;&#x6B63;&#x5E38; B &#x7EC6;&#x80DE;&#x7EC8;&#x7AEF;&#x5206;&#x5316;&#xFF0C;&#x56E0;&#x6B64;&#x4EE3;&#x8868;&#x65B0;&#x578B;&#x5206;&#x5B50;&#x75C5;&#x53D8;&#xFF0C;&#x4EE5;&#x53CA;&#x6F5C;&#x5728;&#x7684;&#x6CBB;&#x7597;&#x9776;&#x70B9; HL &#x6240;&#x8D21;&#x732E;&#x7684;&#x8868;&#x578B;&#x7EF4;&#x4FEE;&#x548C;&#x53D1;&#x75C5;&#x673A;&#x5236;&#x7684; HRS &#x7EC6;&#x80DE;&#x3002;

PRDM1/&#x98DE;&#x8247;-1 &#x970D;&#x5947;&#x91D1;/&#x91CC;&#x5FB7;-&#x65AF;&#x6ED5;&#x4F2F;&#x683C;&#x7EC6;&#x80DE;&#x4ECB;&#x5BFC; MicroRNA &#x4E0B;&#x8C03;&#xFF1A; &#x970D;&#x5947;&#x91D1;&#x6DCB;&#x5DF4;&#x7624;&#x7684;&#x6F5C;&#x5728;&#x81F4;&#x75C5;&#x6027;&#x75C5;&#x53D8;&#x3002;

PRDM1/Blimp-1, a master regulator in terminal B-cell differentiation, has been recently identified as a tumor suppressor target for mutational inactivation in diffuse large B-cell lymphomas of the activated B-cell type. Our studies here demonstrate that PRDM1/blimp-1 is also a target for microRNA (miRNA)-mediated down-regulation by miR-9 and let-7a in Hodgkin/Reed-Sternberg (HRS) cells of Hodgkin lymphoma (HL). MiRNA expression profiling by direct miRNA cloning demonstrated that both of these miRNAs are among the most highly expressed in cultured HRS cells. These miRNAs functionally targeted specific binding sites in the 3' untranslated region of PRDM1/blimp-1 mRNA and repressed luciferase reporter activities through repression of translation. In addition, high levels of miR-9 and let-7a in HL cell lines correlated with low levels of PRDM1/Blimp-1. Similar to their in vitro counterparts, the majority of HRS cells in primary HL cases showed weak or no PRDM1/Blimp-1 expression. Over-expression of miR-9 or let-7a reduced PRDM1/Blimp-1 levels in U266 cells by 30% to 50%, whereas simultaneous inhibition of their activities in L428 cells resulted in an approximately 2.6-fold induction in PRDM1/Blimp-1. MiRNA-mediated down-regulation of PRDM1/Blimp-1 may contribute to the phenotype maintenance and pathogenesis of HRS cells by interfering with normal B-cell terminal differentiation, thus representing a novel molecular lesion, as well as a potential therapeutic target in HL.

MicroRNA-mediated down-regulation of PRDM1/Blimp-1 in Hodgkin/Reed-Sternberg cells: a potential pathogenetic lesion in Hodgkin lymphomas.

PRDM1/Blimp-1, un r&#xE9;gulateur de ma&#xEE;tre dans le terminal B-diff&#xE9;renciation des cellules, a &#xE9;t&#xE9; r&#xE9;cemment identifi&#xE9; comme une cible suppresseur de tumeur pour l&#x26;#39;inactivation mutationnelle dans diffus &#xE0; grandes cellules B des lymphomes de l&#x26;#39;activation des cellules B de type. Nos &#xE9;tudes d&#xE9;montrent que PRDM1/blimp-1 ici est aussi une cible pour les microARN (miARN) m&#xE9;di&#xE9;e par une r&#xE9;gulation par miR-9 et laissez-7a Hodgkin / Reed-Sternberg (HRS) des cellules de lymphome de Hodgkin (LH). Profilage de l&#x26;#39;expression des miARN par clonage miARN directe d&#xE9;montr&#xE9; que ces deux miARN sont parmi les plus fortement exprim&#xE9;s dans les cellules cultiv&#xE9;es HRS. Ces miARN fonctionnellement cibl&#xE9;es sp&#xE9;cifiques des sites de liaison dans la r&#xE9;gion non traduite 3 &#x26;#39;de l&#x26;#39;ARNm et PRDM1/blimp-1 refoul&#xE9;s activit&#xE9;s rapporteur de la lucif&#xE9;rase par la r&#xE9;pression de la traduction. En outre, des niveaux &#xE9;lev&#xE9;s de miR-9 et laissez-7a dans des lign&#xE9;es cellulaires HL en corr&#xE9;lation avec de faibles niveaux de PRDM1/Blimp-1. Semblable &#xE0; leur homologues dans in vitro, la majorit&#xE9; des cellules HRS dans les cas HL primaires ont montr&#xE9; une faible ou aucune expression PRDM1/Blimp-1. La surexpression de miR-9 ou laissez-7a r&#xE9;duite PRDM1/Blimp-1 niveaux dans les cellules U266 de 30% &#xE0; 50%, alors que l&#x26;#39;inhibition simultan&#xE9;e de leurs activit&#xE9;s dans des cellules L428 abouti &#xE0; une induction d&#x26;#39;environ 2,6 fois dans PRDM1/Blimp- 1. MiARN m&#xE9;di&#xE9;e r&#xE9;gulation &#xE0; la baisse des PRDM1/Blimp-1 peut contribuer au maintien de ph&#xE9;notype et de la pathogen&#xE8;se de cellules HRS en interf&#xE9;rant avec la diff&#xE9;renciation terminale des cellules B normales, ce qui repr&#xE9;sente une l&#xE9;sion mol&#xE9;culaire novateur, ainsi que d&#x26;#39;une cible th&#xE9;rapeutique potentielle dans HL.

Micro-ARN m&#xE9;di&#xE9;e par la r&#xE9;gulation n&#xE9;gative de PRDM1/Blimp-1 dans hodgkiniens / cellules Reed-Sternberg: une l&#xE9;sion pathog&#xE9;n&#xE9;tique potentiel dans les lymphomes hodgkiniens

PRDM1/Blimp-1, ein master Regler im terminal B-Zell-Differenzierung, wurde vor kurzem als Tumorsuppressor Ziel f&uuml;r teilhabende Inaktivierung in diffusen gro&szlig;en B-Zell-Lymphome von der aktivierten B-Zell-Typ erkannt. Hier unsere Studien zeigen, dass PRDM1/Blimp-1 auch ein Ziel f&uuml;r MicroRNA (MiRNA ist)-vermittelte Herunterregulation von MiR-9 und lassen-7a in Hodgkin/Reed-Sternberg (HRS) Zellen des Hodgkin-Lymphom (HL). MiRNA Expression profiling durch direkte MiRNA Klonen zeigten, dass beide diese MiRNAs zu den bedeutendsten hoch in kultivierten HRS-Zellen exprimiert werden. Diese MiRNAs funktional gezielt bestimmte Bindungsstellen in der 3&#39; un&uuml;bersetzte Region PRDM1/Blimp-1 mRNA und unterdr&uuml;ckt Luciferase Reporter Aktivit&auml;ten durch Unterdr&uuml;ckung der &Uuml;bersetzung. Hohes Ma&szlig; an MiR-9 und lassen-7a in HL Zelle zus&auml;tzlich Linien korreliert mit niedrigen PRDM1/Blimp-1. &Auml;hnlich wie in-vitro-Gegenst&uuml;cke, die Mehrheit der HRS-Zellen in prim&auml;ren HL F&auml;llen zeigte schwache oder keine PRDM1/Blimp-1-Ausdruck. &Uuml;berexpression von MiR-9 oder lassen-7a reduziert PRDM1/Blimp-1 Ebenen in den U266 Zellen von 30 % bis 50 %, w&auml;hrend gleichzeitige Hemmung ihrer Aktivit&auml;ten im L428 Zellen eine etwa 2.6-fold Induktion in PRDM1/Blimp-1 gef&uuml;hrt. MiRNA-vermittelten Herunterregulation PRDM1/Blimp-1 kann der Ph&auml;notyp Instandhaltung und Pathogenese der HRS-Zellen beitragen, durch Eingriffe in normalen B-terminal Zelldifferenzierung, somit, eine neuartige Molekulare L&auml;sion, sowie m&ouml;gliche therapeutische Ziel in HL.

MicroRNA-vermittelte Herunterregulation PRDM1/Blimp-1 in Hodgkin/Reed-Sternberg-Riesenzellen: eine m&ouml;gliche pathogenetische L&auml;sion in Hodgkin-Lymphome.

PRDM1/Blimp-1, un regolatore master nel terminale differenziazione delle cellule B, &egrave; stata recentemente identificata come una destinazione di soppressore tumorale per inattivazione mutazionale nei linfomi a cellule B grandi diffusi del tipo delle cellule di B attivata. Qui i nostri studi dimostrano che PRDM1/blimp-1 &egrave; anche una destinazione per microRNA (miRNA)-mediated down-regulation di miR-9 e let-7a in cellule di Hodgkin/Reed-Sternberg (HRS) di linfoma di Hodgkin (HL). MiRNA expression profiling di clonazione diretta miRNA hanno dimostrato che entrambi questi miRNAs sono tra i pi&ugrave; altamente espresso in cellule coltivate HRS. Questi miRNAs funzionalmente mirati siti leganti specifici nella regione 3&#39; non tradotte di PRDM1/blimp-1 mRNA e represse le attivit&agrave; di reporter di luciferase attraverso la repressione della traduzione. Inoltre, alti livelli di miR-9 e let-7a in HL cell lines correlato con bassi livelli di PRDM1/Blimp-1. Simili alle loro controparti in vitro, la maggior parte delle cellule HRS in casi primari HL ha mostrato espressione debole o non PRDM1, Blimp-1. Sovraespressione di miR-9 o let-7a ridotto i livelli di PRDM1/Blimp-1 nelle cellule U266 dal 30% al 50%, considerando che la simultanea inibizione delle loro attivit&agrave; nelle cellule L428 ha provocato un&#39; per circa induzione PRDM1/Blimp-1. MiRNA-mediated down-regulation di PRDM1/Blimp-1 pu&ograve; contribuire al mantenimento del fenotipo e patogenesi delle cellule HRS interferendo con la normale differenziazione terminale B-cellula, rappresentando cos&igrave; una romanzo lesione molecolare, cos&igrave; come un potenziale target terapeutico in HL.

MicroRNA-mediated down-regulation di PRDM1/Blimp-1 nelle cellule di Hodgkin/Reed-Sternberg: una lesione potenziale patogenetica in linfomi di Hodgkin.

PRDM1/Blimp-1&#x3001;&#x7AEF;&#x672B;B&#x7D30;&#x80DE;&#x5206;&#x5316;&#x306E;&#x30DE;&#x30B9;&#x30BF;&#x30FC;&#x30EC;&#x30AE;&#x30E5;&#x30EC;&#x30FC;&#x30BF;&#x306F;&#x3001;&#x6700;&#x8FD1;&#x3067;&#x306F;&#x6D3B;&#x6027;&#x5316;B&#x7D30;&#x80DE;&#x578B;&#x306E;&#x3073;&#x307E;&#x3093;&#x6027;&#x5927;&#x7D30;&#x80DE;&#x578B;B&#x7D30;&#x80DE;&#x30EA;&#x30F3;&#x30D1;&#x816B;&#x306B;&#x304A;&#x3051;&#x308B;&#x7A81;&#x7136;&#x5909;&#x7570;&#x4E0D;&#x6D3B;&#x6027;&#x5316;&#x306E;&#x305F;&#x3081;&#x306E;&#x816B;&#x760D;&#x6291;&#x5236;&#x306E;&#x30BF;&#x30FC;&#x30B2;&#x30C3;&#x30C8;&#x3068;&#x3057;&#x3066;&#x540C;&#x5B9A;&#x3055;&#x308C;&#x3066;&#x3044;&#x308B;&#x3002;&#x3053;&#x3053;&#x3067;&#x6211;&#x3005;&#x306E;&#x7814;&#x7A76;&#x306F;&#x3001;PRDM1/blimp-1&#x3082;&#x30DE;&#x30A4;&#x30AF;&#x30ED;RNA&#x306E;&#x6A19;&#x7684;&#xFF08;miRNA&#xFF09;&#x304C;&#x5A92;&#x4ECB;&#x306E;miR-9&#x30DB;&#x30B8;&#x30AD;&#x30F3;/&#x30EA;&#x30FC;&#x30C9;&#xB7;&#x30B7;&#x30E5;&#x30C6;&#x30EB;&#x30F3;&#x30D9;&#x30EB;&#x30AF;&#xFF08;HRS&#xFF09;&#x30DB;&#x30B8;&#x30AD;&#x30F3;&#x30EA;&#x30F3;&#x30D1;&#x816B;&#xFF08;HL&#xFF09;&#x306E;&#x7D30;&#x80DE;&#x306B;&#x304A;&#x3051;&#x308B;let-7a&#x3092;&#x306B;&#x3088;&#x3063;&#x3066;&#x30C0;&#x30A6;&#x30F3;&#x30EC;&#x30AE;&#x30E5;&#x30EC;&#x30FC;&#x30B7;&#x30E7;&#x30F3;&#x3067;&#x3042;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x3057;&#x3066;&#x3044;&#x308B;&#x3002;&#x76F4;&#x63A5;&#x306E;miRNA&#x306E;&#x30AF;&#x30ED;&#x30FC;&#x30CB;&#x30F3;&#x30B0;&#x306B;&#x3088;&#x308B;miRNA&#x767A;&#x73FE;&#x30D7;&#x30ED;&#x30D5;&#x30A1;&#x30A4;&#x30EA;&#x30F3;&#x30B0;&#x306F;&#x3001;&#x3053;&#x308C;&#x3089;&#x306E;miRNA&#x306E;&#x4E21;&#x65B9;&#x304C;&#x6700;&#x3082;&#x9AD8;&#x3044;&#x57F9;&#x990A;HRS&#x7D30;&#x80DE;&#x3067;&#x767A;&#x73FE;&#x306E;&#x9593;&#x306B;&#x3042;&#x308B;&#x3053;&#x3068;&#x3092;&#x5B9F;&#x8A3C;&#x3057;&#x305F;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;miRNA&#x306F;&#x3001;&#x6A5F;&#x80FD;&#x7684;&#x306B;&#x7FFB;&#x8A33;&#x306E;&#x6291;&#x5236;&#x3092;&#x4ECB;&#x3057;&#x3066;PRDM1/blimp-1 mRNA&#x3068;&#x6291;&#x5727;&#x30EB;&#x30B7;&#x30D5;&#x30A7;&#x30E9;&#x30FC;&#x30BC;&#x30EC;&#x30DD;&#x30FC;&#x30BF;&#x30FC;&#x6D3B;&#x6027;&#x306E;3 &#x26;#39;&#x975E;&#x7FFB;&#x8A33;&#x9818;&#x57DF;&#x5185;&#x306E;&#x7279;&#x5B9A;&#x306E;&#x7D50;&#x5408;&#x90E8;&#x4F4D;&#x3092;&#x5BFE;&#x8C61;&#x3068;&#x3057;&#x305F;&#x3002;&#x3055;&#x3089;&#x306B;&#x3001;HL&#x7D30;&#x80DE;&#x682A;&#x3067;&#x306E;miR-9&#x304A;&#x3088;&#x3073;let-7a&#x306E;&#x9AD8;&#x30EC;&#x30D9;&#x30EB;&#x306E;PRDM1/Blimp-1&#x306E;&#x4F4E;&#x30EC;&#x30D9;&#x30EB;&#x3068;&#x76F8;&#x95A2;&#x3057;&#x3066;&#x3044;&#x305F;&#x3002;&#x305D;&#x308C;&#x3089;&#x306E;in vitro&#x3067;&#x306E;&#x5BFE;&#x5FDC;&#x3067;&#x3068;&#x540C;&#x69D8;&#x306B;&#x3001;&#x30D7;&#x30E9;&#x30A4;&#x30DE;&#x30EA;HL&#x30B1;&#x30FC;&#x30B9;&#x3067;HRS&#x7D30;&#x80DE;&#x306E;&#x5927;&#x90E8;&#x5206;&#x304C;&#x5F31;&#x3044;&#x3001;&#x3042;&#x308B;&#x3044;&#x306F;&#x307E;&#x3063;&#x305F;&#x304F;PRDM1/Blimp-1&#x767A;&#x73FE;&#x3092;&#x793A;&#x3057;&#x305F;&#x3002; L428&#x7D30;&#x80DE;&#x5185;&#x306E;&#x6D3B;&#x52D5;&#x306E;&#x540C;&#x6642;&#x963B;&#x5BB3;&#x304C;&#x3001;&#x7D04;2.6&#x500D;&#x8A98;&#x5C0E;&#x3055;&#x308C;&#x305F;&#x4E00;&#x65B9;&#x306E;miR-9&#x307E;&#x305F;&#x306F;let-7a&#x306E;&#x904E;&#x5270;&#x767A;&#x73FE;&#x306F;&#x3001;30&#xFF05;&#x301C;50&#xFF05;&#x3067;U266&#x7D30;&#x80DE;&#x5185;PRDM1/Blimp-1&#x30EC;&#x30D9;&#x30EB;&#x3092;&#x6E1B;&#x5C11;&#x3055;&#x305B;&#x305F;PRDM1/Blimp- 1&#x3002; PRDM1/Blimp-1&#x306E;miRNA-&#x4ECB;&#x5728;&#x306E;&#x30C0;&#x30A6;&#x30F3;&#x30EC;&#x30AE;&#x30E5;&#x30EC;&#x30FC;&#x30B7;&#x30E7;&#x30F3;&#x306F;&#x3001;&#x3053;&#x306E;&#x3088;&#x3046;&#x306B;&#x65B0;&#x898F;&#x306E;&#x5206;&#x5B50;&#x75C5;&#x5909;&#x3068;&#x540C;&#x69D8;&#x306B;&#x3001;HL&#x306E;&#x6CBB;&#x7642;&#x6A19;&#x7684;&#x3068;&#x306A;&#x308B;&#x53EF;&#x80FD;&#x6027;&#x3092;&#x8868;&#x3059;&#x3001;&#x901A;&#x5E38;&#x306E;B&#x7D30;&#x80DE;&#x306E;&#x5206;&#x5316;&#x3092;&#x963B;&#x5BB3;&#x3059;&#x308B;&#x3053;&#x3068;&#x306B;&#x3088;&#x3063;&#x3066;HRS&#x7D30;&#x80DE;&#x306E;&#x8868;&#x73FE;&#x578B;&#x306E;&#x30E1;&#x30F3;&#x30C6;&#x30CA;&#x30F3;&#x30B9;&#x3084;&#x75C5;&#x56E0;&#x306B;&#x5BC4;&#x4E0E;&#x3059;&#x308B;&#x53EF;&#x80FD;&#x6027;&#x304C;&#x3042;&#x308A;&#x307E;&#x3059;&#x3002;

&#x30DB;&#x30B8;&#x30AD;&#x30F3;&#x30EA;&#x30F3;&#x30D1;&#x816B;/&#x30EA;&#x30FC;&#x30C9;&#xB7;&#x30B7;&#x30E5;&#x30C6;&#x30EB;&#x30F3;&#x30D9;&#x30EB;&#x30AF;&#x7D30;&#x80DE;&#x306B;&#x304A;&#x3051;&#x308B;PRDM1/Blimp-1&#x306E;microRNA&#x306E;&#x5A92;&#x4ECB;&#x30C0;&#x30A6;&#x30F3;&#x30EC;&#x30AE;&#x30E5;&#x30EC;&#x30FC;&#x30B7;&#x30E7;&#x30F3;&#xFF1A;&#x30DB;&#x30B8;&#x30AD;&#x30F3;&#x30EA;&#x30F3;&#x30D1;&#x816B;&#x306B;&#x304A;&#x3051;&#x308B;&#x6F5C;&#x5728;&#x7684;&#x306A;&#x75C5;&#x539F;&#x6027;&#x75C5;&#x5909;

PRDM1/&#xC608; &#xC2A4; &#xB7EC;&#xC6B4;-1 &#xD130;&#xBBF8;&#xB110; B-&#xC138;&#xD3EC; &#xBD84;&#xD654;&#xC5D0; &#xB9C8;&#xC2A4;&#xD130; &#xB808; &#xADE4; &#xB808;&#xC774; &#xD130; &#xCD5C;&#xADFC;&#xC5D0; &#xBC1C;&#xACAC; &#xB418;&#xC5C8;&#xC2B5;&#xB2C8;&#xB2E4; &#xD65C;&#xC131;&#xD654; &#xB41C; B &#xC138;&#xD3EC; &#xD0C0;&#xC785;&#xC758; &#xD655;&#xC0B0; &#xD070; B-&#xC138;&#xD3EC; lymphomas&#xC5D0;&#xC11C; mutational &#xBE44;&#xD65C;&#xC131;&#xD654;&#xC5D0; &#xB300; &#xD55C; &#xC885;&#xC591; &#xC5B5;&#xC81C; &#xB300;&#xC0C1;&#xC73C;&#xB85C;. &#xC5EC;&#xAE30;&#xC5D0; &#xC6B0;&#xB9AC;&#xC758; &#xC5F0;&#xAD6C; &#xBCF4;&#xC5EC; PRDM1/&#xC608; &#xC2A4; &#xB7EC;&#xC6B4;-1 microRNA (&#xBBF8;&#xB974;)&#xC758; &#xB300;&#xC0C1; &#xC774;&#xAE30;&#xB3C4;-&#xB2E4;&#xC6B4; &#xB808; &#xADE4; &#xB808;&#xC774; &#xC158; &#xBBF8;&#xB974;-9 &#xACE0; &#xD558;&#xC790;-7a Hodgkin &#xB9BC;&#xD504; &#xC885; (HL)&#xC758; &#xC140; Hodgkin/&#xB9AC;&#xB4DC;-&#xC2A4;&#xD134; (&#xC2DC;&#xAC04;)&#xC5D0; &#xC758;&#xD574; &#xC911;&#xC7AC;. &#xBBF8;&#xB974; &#xC2DD; &#xC9C1;&#xC811; &#xBBF8;&#xB974; &#xBCF5;&#xC81C; &#xD558; &#xC5EC; &#xD504;&#xB85C; &#xD30C;&#xC77C;&#xB9C1;&#xC744; &#xBAA8;&#xB450; &#xC774;&#xB7EC;&#xD55C; miRNAs &#xAC00;&#xC6B4;&#xB370; &#xAC00;&#xC7A5; &#xB192;&#xC740;&#xC5D0;&#xC11C; &#xD45C;&#xD604; &#xB418;&#xB294; &#xAD50;&#xC591;&#xB41C; &#xC2DC;&#xAC04; &#xC140; &#xC2DC;&#xC5F0; &#xD588;&#xB2E4;. &#xC774;&#xB7EC;&#xD55C; Mirnas&#xB294; &#xAE30;&#xB2A5;&#xC801;&#xC73C;&#xB85C; PRDM1/&#xC608; &#xC2A4; &#xB7EC;&#xC6B4;-1 Mrna&#xC758; 3&#39; &#xB9DE;&#xC774; &#xC9C0;&#xC5ED;&#xC5D0;&#xC11C; &#xD2B9;&#xC815; &#xBC14;&#xC778;&#xB529; &#xC0AC;&#xC774;&#xD2B8;&#xB97C; &#xB300;&#xC0C1;&#xC73C;&#xB85C; &#xD558; &#xACE0; &#xBC88;&#xC5ED;&#xC758; &#xC5B5;&#xC81C;&#xB97C; &#xD1B5;&#xD574; &#xB8E8;&#xC2DC;&#xD398;&#xB77C;&#xC544;&#xC81C; &#xAE30;&#xC790; &#xD65C;&#xB3D9;&#xC744; &#xC5B5;&#xC555;. &#xB610;&#xD55C;, &#xB192;&#xC740; &#xC218;&#xC900;&#xC758; &#xBBF8;&#xB974; 9 &#xBC0F; HL&#xC5D0; &#xD558;&#xC790;-7a &#xC140; &#xB77C;&#xC778; PRDM1/&#xC608; &#xC2A4; &#xB7EC;&#xC6B4;-1 &#xB0AE;&#xC740; &#xC218;&#xC900;&#xC758; &#xC0C1;&#xD638; &#xC5F0;&#xAD00;. &#xC2DC;&#xD5D8;&#xAD00; &#xB4E4;&#xACFC; &#xB9C8;&#xCC2C;&#xAC00;&#xC9C0;&#xB85C;, &#xC2DC;&#xAC04; &#xC140; &#xAE30;&#xBCF8; HL&#xC758; &#xACBD;&#xC6B0;&#xC5D0;&#xC11C; &#xB300;&#xBD80;&#xBD84; &#xC57D;&#xD558;&#xAC70;&#xB098; &#xB354; PRDM1/&#xC608; &#xC2A4; &#xB7EC;&#xC6B4;-1 &#xC2DD;&#xC73C;&#xB85C; &#xB098;&#xD0C0;&#xB0AC;&#xB2E4;. &#xBBF8;&#xB974; 9 &#xB610;&#xB294; &#xD558;&#xC790; 7a over-expression PRDM1/&#xC608; &#xC2A4; &#xB7EC;&#xC6B4;-1&#xC5D0;&#xC11C; &#xC57D; 2.6-fold &#xC720;&#xB3C4; &#xADC0;&#xCC29;&#xB418; &#xC5C8; &#xB2E4; L428 &#xC138;&#xD3EC;&#xC5D0;&#xC11C; &#xADF8;&#xB4E4;&#xC758; &#xD65C;&#xB3D9;&#xC758; &#xB3D9;&#xC2DC; &#xC800;&#xD574; &#xD558;&#xB294; &#xBC18;&#xBA74; 30%&#xC5D0;&#xC11C; 50%&#xB85C;, U266 &#xC140;&#xC5D0; PRDM1/&#xC608; &#xC2A4; &#xB7EC;&#xC6B4;-1 &#xB808;&#xBCA8; &#xAC10;&#xC18C;. PRDM1/&#xC608; &#xC2A4; &#xB7EC;&#xC6B4;-1 &#xB2E4;&#xC6B4; &#xADDC;&#xC81C; MiRNA &#xC911;&#xC7AC;&#xB294; &#xB530;&#xB77C;&#xC11C; HL&#xC5D0; &#xC7A0;&#xC7AC;&#xC801;&#xC778; &#xCE58;&#xB8CC; &#xB300;&#xC0C1;&#xC73C;&#xB85C; &#xC18C;&#xC124; &#xBD84;&#xC790; &#xBCD1; &#xBCC0; &#xB300;&#xD45C; &#xC815;&#xC0C1; B &#xC138;&#xD3EC; &#xD130;&#xBBF8;&#xB110; &#xBD84;&#xD654;&#xB97C; &#xBC29;&#xD574; &#xD558; &#xC5EC; &#xD45C;&#xD604; &#xD615; &#xC720;&#xC9C0; &#xBCF4;&#xC218; &#xBC0F; &#xC2DC;&#xAC04; &#xC140;&#xC758; pathogenesis &#xAE30;&#xC5EC;&#xD560; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;.

PRDM1/&#xC608; &#xC2A4; &#xB7EC;&#xC6B4;-1 Hodgkin/&#xB9AC;&#xB4DC;-&#xC2A4;&#xD134; &#xC140;&#xC5D0;&#xC11C;&#xC758; &#xB2E4;&#xC6B4; &#xADDC;&#xC81C; MicroRNA &#xC911;&#xC7AC;: Hodgkin lymphomas&#xC5D0; &#xC7A0;&#xC7AC;&#xC801;&#xC778; pathogenetic &#xBCD1; &#xBCC0;.

PRDM1/Blimp-1, un regulador maestro de la terminal B-diferenciaci&#xF3;n celular, ha sido recientemente identificado como un objetivo supresor de tumores para la inactivaci&#xF3;n de las mutaciones en el difuso de c&#xE9;lulas B grandes linfomas de c&#xE9;lulas B activadas tipo. Nuestros estudios demuestran que aqu&#xED; PRDM1/blimp-1 es tambi&#xE9;n un objetivo para los microRNA (miRNA) mediada por la regulaci&#xF3;n a la baja por el MIR-9 y let-7a de Hodgkin / Reed-Sternberg (HRS), las c&#xE9;lulas del linfoma de Hodgkin (LH). Perfiles de expresi&#xF3;n de miRNA por clonaci&#xF3;n directa miARN demostrado que tanto de estos miRNAs est&#xE1;n entre las m&#xE1;s altamente expresado en c&#xE9;lulas cultivadas HRS. Estos miRNAs funcionalmente dirigido sitios de uni&#xF3;n espec&#xED;ficos en la regi&#xF3;n no traducida 3 &#x26;#39;del ARNm y PRDM1/blimp-1 reprimidos actividades reportero luciferasa trav&#xE9;s de la represi&#xF3;n de la traducci&#xF3;n. Adem&#xE1;s, los altos niveles de MIR-9 y dejar 7a-en l&#xED;neas de c&#xE9;lulas HL correlacionado con niveles bajos de PRDM1/Blimp-1. Similar a su contraparte en in vitro, la mayor&#xED;a de las c&#xE9;lulas primarias HRS en casos HL mostr&#xF3; expresi&#xF3;n PRDM1/Blimp-1 d&#xE9;bil o no. La sobre-expresi&#xF3;n de miR-9 o dejar 7a-reduce los niveles de PRDM1/Blimp-1 en c&#xE9;lulas U266 en un 30% a 50%, mientras que la inhibici&#xF3;n simult&#xE1;nea de sus actividades en las c&#xE9;lulas L428 dio lugar a una inducci&#xF3;n de alrededor de 2,6 veces en el PRDM1/Blimp- 1. MIRNA mediada baja regulaci&#xF3;n de PRDM1/Blimp-1 puede contribuir al mantenimiento fenotipo y patog&#xE9;nesis de las c&#xE9;lulas HRS al interferir con la diferenciaci&#xF3;n normal terminal de c&#xE9;lulas B, por lo que representa una lesi&#xF3;n molecular nuevo, as&#xED; como una diana potencial terap&#xE9;utico en HL.

Micro RNA mediada por Down-regulaci&#xF3;n de PRDM1/Blimp-1 de Hodgkin / Reed-Sternberg c&#xE9;lulas: una lesi&#xF3;n patog&#xE9;nico potencial en los linfomas de Hodgkin

To perform phylogenetic analysis of Mycoplasma suis isolates derived from China to define the nature of this pathogen, nearly complete of 16S rRNA genes from Chongqing, Sichuan, Henan and Guangdong isolates were amplified by PCR and sequenced. The four sequences from the blood samples in this study, with other 17 Hemoplasmas sequences and related 3 mycoplasma sequences available in the GenBank, were aligned using Clustal X (version 1.83) sequences alignment program. Maximum parsimony, neighbor-joining and minimum evolution (MEGA 4.0) algorithms were used to create phylogenetic trees. Phylogenetic analysis of these sequences showed that all hemoplasma species were located within a single clade and were most closely related to M. pneumoniae group. The hemoplasma species were further subdivided into two distinct groups, one containing M.wenyonii, M.suis and Candidatus M. haemominutum and the other containing M. haemofelis and M. haemocanis. Within the former clade, four M.suis isolates from Mainland China and other M.suis species formed a monophyletic group in the tree. A tendency of clear geographical grouping of the isolate was evident.

Phylogenetic analysis of Mycoplasma suis isolates based on 16S rRNA gene sequence in China.

To identify the species within the genus Anaplasma circulating among ruminants in the Southwest of China, we performed the phylogenetic analysis of the 16S rRNA gene of two Anaplasma isolates from cattle and seven from goats. The two sequences obtained from cattle strains belonged to the A. marginale cluster, whereas the other seven sequences from caprine strains formed two Anaplasma spp. clusters, which diverged earlier than the clusters of A. marginale, A. centrale and A. ovis. These results indicate that there are at least two Anaplasma species circulating among ruminants in Southwestern China.

Phylogenetic analysis of the genus Anaplasma in Southwestern China based on 16S rRNA sequence.

PRDM1/Blimp-1, a master regulator for B cell terminal differentiation, is a putative tumor suppressor in diffuse large B cell lymphomas (DLBCL). Inactivating mutations of PRDM1 have been previously identified in a subset of nongerminal center B cell-like (GCB) DLBCL. We investigated the presence of alternative mechanisms of down-regulating PRDM1 in a cohort of 25 primary DLBCL and six DLBCL cell lines. While some DLBCL, predominantly the GCB-type, showed low levels of both PRDM1alpha mRNA and protein, presumably as a result of direct transcription repression, discordant expressions between the two were identified in a subset of DLBCL without PRDM1 mutations, the primarily non-GCB type, consistent with translational down-regulation. This subset of DLBCL exhibits relatively high PRDM1alpha mRNA levels but low levels of PRDM1. Data obtained from expression analysis, luciferase reporter assays, and transfection experiments support a role of targeting of PRDM1 by microRNA let-7 family in mediating this down-regulation. Let-7, in particular let-7b, is overexpressed in DLBCL relative to normal GCB cells, suggesting that it is deregulated. Thus, abnormal epigenetic down-regulation of PRDM1 by let-7 and other microRNAs may represent an alternative mechanism of reducing normal PRDM1 function in a subset of DLBCL with relatively high PRDM1alpha mRNA expression and unmutated PRDM1. These findings provide further evidence for an important role of impairment of terminal B cell differentiation in DLBCL pathogenesis.

Epigenetic down-regulation of the tumor suppressor gene PRDM1/Blimp-1 in diffuse large B cell lymphomas: a potential role of the microRNA let-7.

Follicular lymphoma (FL) is an indolent lymphoma that transforms to high-grade lymphoma, mostly diffuse large B-cell lymphoma, in about a third of patients. We present the first report of a case of FL that transformed to plasmablastic lymphoma (PBL). Clonal transformation of the FL to PBL was evidenced by identical IGH/BCL2 gene rearrangements and VDJ gene usage in rearranged IGH genes. IGH/ BCL2 translocation was retained in the PBL, which also acquired c-myc gene rearrangement. Genealogic analysis based on somatic hypermutation of the rearranged IGH genes of both FL and PBL suggests that transformation of the FL to PBL occurred most likely by divergent evolution from a common progenitor cell rather than direct evolution from the FL clone. Our study of this unusual case expands the histologic spectrum of FL transformation and increases our understanding of the pathogenetic mechanisms of transformation of indolent lymphomas to aggressive lymphomas.

Transformation of follicular lymphoma to plasmablastic lymphoma with c-myc gene rearrangement.

Alternatively activated macrophages (AAMφ) play important roles in allergies and responses toparasitic infections. However, whether signaling through toll-like receptors (TLRs) plays any role in AAMφ induction when young Fasciola hepatica penetrates the liver capsule and migrates through the liver tissue is still unclear.

The absence of MyD88 has no effect on the induction of alternatively activated macrophage during Fasciola hepatica infection.

Composite lymphomas (CLs) consisting of 2 indolent B-cell lymphomas are rare. We present 2 CL cases composed of chronic lymphocytic leukemia (CLL) and follicular lymphoma (FL), each with unique clinicopathologic features. In the first case, the FL was negative for IGH-BCL2 and harbored a novel IGH-associated translocation; in the second case, the CL manifested in the skin. The individual components in both CLs were derived from different B-cell clones. This is the first complete characterization, including molecular analysis, of CLs composed of leukemic CLL and FL and the first report of a cutaneous CL derived from 2 low-grade B cell lymphomas. Our results provide additional supporting evidence that CLs of indolent B-cell lymphomas are biclonal and suggest that they are pathogenetically different from CLs composed of a low-grade B-cell lymphoma and an aggressive B-cell lymphoma or Hodgkin lymphoma, which are usually clonally related.

Composite chronic lymphocytic leukemia/small lymphocytic lymphoma and follicular lymphoma are biclonal lymphomas: a report of two cases.

Coccidiosis, caused by Eimeria parasites, is a major parasitic disease responsible for great economic losses in the poultry industry. Toll-like receptor (TLR) family is one of the most important innate immune receptors, which involved in pathogen detection by initiating host responses, and it plays important roles in the reduction and clearance of pathogens. Very little information is available about the roles of chicken TLRs (ChTLRs) during Eimeria tenella infection. In the current study, mRNA expression of ChTLRs and associated signal adaptors in heterophils and monocyte-derived macrophages stimulated with E. tenella in vitro were measured by real-time quantitative polymerase chain reaction. The results showed that ChTLR4 and ChTLR15 expression were increased significantly in heterophils and monocyte-derived macrophages following live E. tenella sporozoites stimulation. The heat-killed E. tenella sporozoites stimulated higher expression of ChTLRs and signal adaptors than live sporozoites, the expression of ChTLR4, ChTLR15 and MyD88 in heterophils and monocyte-derived macrophages stimulated with heat-killed E. tenella sporozoites were up-regulated significantly than unstimulated cells. The results suggest that ChTLR4 and ChTLR15 are involved in response to E. tenella infection, and may operate in a MyD88-dependent manner for host defense.

Upregulation of chicken TLR4, TLR15 and MyD88 in heterophils and monocyte-derived macrophages stimulated with Eimeria tenella in vitro.

Molecular mechanisms associated with frequent relapse of diffuse large B-cell lymphoma (DLBCL) are poorly defined. It is especially unclear how primary tumor clonal heterogeneity contributes to relapse. Here, we explore unique features of B-cell lymphomas - VDJ recombination and somatic hypermutation - to address this question.

Deep sequencing reveals clonal evolution patterns and mutation events associated with relapse in B-cell lymphomas.

The contribution of epigenomic alterations to tumour progression and relapse is not well characterized. Here we characterize an association between disease progression and DNA methylation in diffuse large B-cell lymphoma (DLBCL). By profiling genome-wide DNA methylation at single-base pair resolution in thirteen DLBCL diagnosis-relapse sample pairs, we show that DLBCL patients exhibit heterogeneous evolution of tumour methylomes during relapse. We identify differentially methylated regulatory elements and determine a relapse-associated methylation signature converging on key pathways such as transforming growth factor-β (TGF-β) receptor activity. We also observe decreased intra-tumour methylation heterogeneity from diagnosis to relapsed tumour samples. Relapse-free patients display lower intra-tumour methylation heterogeneity at diagnosis compared with relapsed patients in an independent validation cohort. Furthermore, intra-tumour methylation heterogeneity is predictive of time to relapse. Therefore, we propose that epigenomic heterogeneity may support or drive the relapse phenotype and can be used to predict DLBCL relapse.

Kui Nie

Department of Pathology and Laboratory Medicine

Weill Cornell Medical College

VDJ-Seq: Deep Sequencing Analysis of Rearranged Immunoglobulin Heavy Chain Gene to Reveal Clonal Evolution Patterns of B Cell Lymphoma

Kui Nie

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Pathology and Laboratory Medicine

Weill Cornell Medical College

VDJ-Seq: Deep Sequencing Analysis of Rearranged Immunoglobulin Heavy Chain Gene to Reveal Clonal Evolution Patterns of B Cell Lymphoma

Department of Pathology and Laboratory Medicine