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DIAGNOSI E TERAPIA DELLE LEUCEMIE LINFOBLASTICHE ACUTE e

DIAGNOSI E TERAPIA DELLE LEUCEMIE LINFOBLASTICHE ACUTE e DELLE SINDROMI LINFOPROLIFERATIVE CRONICHE, DEI LINFOMI E DEL MIELOMA MULTIPLO Giovanni Martinelli, MD Istituto di Ematologia e Oncologia Medica L. & A. Seràgnoli, Università degli Studi di Bologna. ALL. DANNO GENETICO.

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DIAGNOSI E TERAPIA DELLE LEUCEMIE LINFOBLASTICHE ACUTE e

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  1. DIAGNOSI E TERAPIA DELLE LEUCEMIE LINFOBLASTICHE ACUTE e DELLE SINDROMI LINFOPROLIFERATIVE CRONICHE, DEI LINFOMI E DEL MIELOMA MULTIPLO Giovanni Martinelli, MD Istituto di Ematologia e Oncologia Medica L. & A. Seràgnoli, Università degli Studi di Bologna

  2. ALL DANNO GENETICO ANLL o AML

  3. L’analisi molecolare: • Identifica gruppi di pazienti con diversa prognosi • Anomalie genetiche non citogeneticamente identificate o caratterizzate • Significato clinico diverso della persistenza di MMR • Livelli di malattia minima residua assai piccoli. • Suggerisce la risposta alla chemioterapia • Meccanismi molecolari sconosciuti.

  4. Geni non di Fusione Si definiscono geni non di fusione gli oncogeni associati a traslocazioni cromosomiche specifiche, generati dalla ricombinazione tra due geni. Danno origine a m-RNA neoplastici, il cui prodotto e’ spesso over espresso ed e’ oncogeno anche se solo uno dei due geni e’ funzionante. Un tipico esempio e’ l’oncogene Myc associato alla traslocazione t(8;14) Istituto di Ematologia ed Oncologia Medica “Seràgnoli”, Bologna

  5. GENI NON DI FUSIONE A C C R R C B R

  6. Geni di Fusione Si definiscono geni di fusione gli oncogeni associati a traslocazioni cromosomiche specifiche, generati dalla ricombinazione tra due geni. Danno origine a m-RNA chimerici il cui prodotto e’ espresso ed e’ neoplastico se entrambi i due oncogeni sono funzionanti. Un tipico esempio e’ l’oncogene BCR-ABL associato alla traslocazione t(9;22) ed alla Leucemia Mieloide Cronica, oppure l’oncogene PML-RAR alfa associato alla t(15;17) ed alla Leucemia Acuta a promielociti. Istituto di Ematologia ed Oncologia Medica “Seràgnoli”

  7. GENI DI FUSIONE C C R R C3’ C5’ R

  8. Acute Lymphoid Leukemia

  9. FREQUENCY OF PRINCIPAL TRANSLOCATION AND FUSION GENEs IN ALL

  10. ALL

  11. Principali alterazioni molecolari e fusion gene e loro frequenza nelle ALL • none 19% • random 25% • BCR-ABL 4% • TEL-AML1 28% • MLL fusions 6% • 11q23 (AMLL1/Htrx/Hrx/ALL-1) 13 (1% ) • E2A-PBX 1% Istituto di Ematologia ed Oncologia Medica “Seragnoli”, Bologna

  12. Estimated Frequency of Specific Genotypes of ALL in Children and Adults.

  13. Transformation of Hematopoietic Cells in the Pathogenesis of ALL.

  14. Mechanism of Transcriptional Repression by TEL-AML1.

  15. The Retinoblastoma (RB) and p53 Tumor-Suppressor Network.

  16. Kaplan–Meier Analysis of Event-free Survival According to the Subtype of Leukemia in 467 Children with ALL Who Were Enrolled in Three Consecutive Treatment Protocols at St. Jude Children's Research Hospital from 1991 to 1999.

  17. Influence of Host Germ-Line and ALL Blast Genotypes on the Probability of Cure and of Adverse Events.

  18. Analisi molecolare: Microarray

  19. Principali alterazioni molecolari e fusion gene e loro frequenza nelle ALL • random 25% • BCR-ABL 4% • TEL-AML1 28% • MLL fusions 6% • 11q23 (AMLL1/Htrx/Hrx/ALL-1) 13 (1% ) • E2A-PBX 1% • none 19% Istituto di Ematologia ed Oncologia Medica “Seragnoli”, Bologna

  20. Is ALL Ph+ homogenous? INDIVIDUAL VARIABILITY?

  21. Struttura dei geni ABL e BCR e sonde utilizzate in FISH a 3 colori e in D-FISH (Oncor) Sinclair et al., Blood 2000; 95:738-744

  22. cen LMX2 NEK6 PSMB7 NR5A1 NR6A1 RPL35 GOLGA1 PPP6C HSPA5 SIN1_HUMAN PBX3 ANGPTL2 SLCA8 RPL12 STXBP1 SH2D3C CDK9 FPGS ENG AK1 SIAT7D DPM2 ZNF297B LMX1B C9orf15 C9orf16 LCN2 CIZ1_HUMAN DNM1 GOLGA2 SLC27A4 ODF2 GLE1L SPTAN1 SET SH3GLB2 CRAT PPP2R4 CCBL1 ENDOG PMX2_HUMAN PTGES DYT1 USP2O FREQ ASS FUBP3 PRDM12 RRP4_HUMAN Prostaglandin E synthase chr.9 tel

  23. CDK9 FPGS ENG AK1 SIAT7D DPM2 ZNF297B LMX1B C9orf15 C9orf16 LCN2 CIZ1_HUMAN DNM1 GOLGA2 SLC27A4 ODF2 GLE1L SPTAN1 SET SH3GLB2 CRAT PPP2R4 CCBL1 ENDOG PMX2_HUMAN PTGES DYT1 USP2O FREQ ASS FUBP3 PRDM12 RRP4_HUMAN ABL LMX2 NEK6 PSMB7 NR5A1 NR6A1 RPL35 GOLGA1 PPP6C HSPA5 SIN1_HUMAN PBX3 ANGPTL2 SLCA8 RPL12 STXBP1 SH2D3C

  24. LMX2 NEK6 PSMB7 NR5A1 NR6A1 RPL35 GOLGA1 PPP6C HSPA5 SIN1_HUMAN PBX3 ANGPTL2 SLCA8 RPL12 STXBP1 SH2D3C CDK9 FPGS ENG AK1 SIAT7D DPM2 ZNF297B LMX1B C9orf15 C9orf16 LCN2 CIZ1_HUMAN DNM1 GOLGA2 SLC27A4 ODF2 GLE1L SPTAN1 SET SH3GLB2 CRAT PPP2R4 CCBL1 ENDOG PMX2_HUMAN PTGES DYT1 USP2O FREQ ASS FUBP3 PRDM12 RRP4_HUMAN LMX2 NEK6 PSMB7 NR5A1 NR6A1 RPL35 GOLGA1 PPP6C HSPA5 SIN1_HUMAN PBX3 ANGPTL2 SLCA8 RPL12 STXBP1 SH2D3C CDK9 FPGS ENG AK1 SIAT7D DPM2 ZNF297B LMX1B C9orf15 C9orf16 LCN2 CIZ1_HUMAN DNM1 GOLGA2 SLC27A4 ODF2 GLE1L SPTAN1 SET SH3GLB2 CRAT PPP2R4 CCBL1 ENDOG PMX2_HUMAN PTGES DYT1 USP2O FREQ ASS FUBP3 PRDM12 RRP4_HUMAN LMX2 NEK6 PSMB7 NR5A1 NR6A1 RPL35 GOLGA1 PPP6C HSPA5 SIN1_HUMAN PBX3 ANGPTL2 SLCA8 RPL12 STXBP1 SH2D3C CDK9 FPGS ENG AK1 SIAT7D DPM2 ZNF297B LMX1B C9orf15 C9orf16 LCN2 CIZ1_HUMAN DNM1 GOLGA2 SLC27A4 ODF2 GLE1L SPTAN1 SET SH3GLB2 CRAT PPP2R4 CCBL1 ENDOG PMX2_HUMAN PTGES DYT1 USP2O FREQ ASS FUBP3 PRDM12 RRP4_HUMAN tel

  25. cen FBXW3 IGLL1 ZNF70 VPREB3 MMP11 SMARCB1 SLC2A11 MIF GSTT2 DDT GSTT1 CABI_HUMAN GGTLA1 SMARCB1: SWI/SNF related, actin dependent regulator ofchromatin subfamily B member 1 GSTT1:Glutathione S-transferase theta 1 tel chr.22

  26. Principali alterazioni molecolari e fusion gene e loro frequenza nelle ALL • random 25% • BCR-ABL 4% • TEL-AML1 28% • MLL fusions 6% • 11q23 (AMLL1/Htrx/Hrx/ALL-1) 1% • E2A-PBX 1% • none 19% Istituto di Ematologia ed Oncologia Medica “Seragnoli”, Bologna

  27. 11q23 and MLL

  28. MLL positive leukemias t(1;11) t(11;19) t(4;11) t(11;22) t(X;11) (q13;q23) t(6;11) t(X;11)(q24;q23) t(9;11) MLL del 11 (q11q23) t(10;11) t(11;17) del 11 (q21q23) Breakpoints in MLL 5 6 7 8 10 12 13 9 11 centromere telomere Zn fingers A-T hooks MT MLL fusion point ENL MLL ENL der 11 chromosome

  29. MLL and Fusion Patners in Leukemia ENL MLL AF10 CALM AFA AF17 AF6q21 AF5q31 ELL AF19 AFX Eps15 ABI ENN MSF AF3q21 AMLL1/Htrx/Hrx/ALL-1 AT PHD MTase BP??

  30. Chr. 8 and t(8;14) and BURKITT LUKEMIA

  31. TRANSLOCATIONS OF c-Myc Locus Reciprocal chromosomal translocations in Burkitt's lymphoma, a solid tumour of B lymphocytes involves chr.14 and chr 8 chr.2 chr 22.

  32. The genes for making the heavy chains of antibodies (CH) are located on chromosomes 14, whereas those for making the light chains are on chromosomes 2 and 22.

  33. Struttura dell’anticorpo

  34. Patologia dell’ sintesi Ig

  35. Struttura dell’anticorpo Le Ig possono essere suddivise in classi o sottoclassi sulla base delle catene pesante ISOTIPI • IgM m • IgA a1 a2 • IgG g1, g2, g3, g4 • IgD d • IgE e

  36. Configurazione geni Ig germinale IgH: Cromosoma 14 Igk: Cromosoma 2 Igl: Cromosoma 22

  37. Riarrangiamento catena leggera

  38. Mapping of cloned germline and rearranged antigen receptor gene segments

  39. Genomic structure of selected antigen receptor loci

  40. Cloning of the V(D)J recombinase genes.

  41. The RAG proteins and the RAG cleavage reaction (A) Schematic of RAG-1 and RAG-2, illustrating known mofits and the putative RAG-1 DDE active site (B) Summary of the RAG cleavage reaction.

  42. V(D)J recombination and the non-homologous end-joining pathway

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