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Il ruolo del next generation sequencing nelle leucemie acute

12 aprile 2013 Bologna. Il ruolo del next generation sequencing nelle leucemie acute. Ilaria Iacobucci. Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna. Genetic characterization of BCR-ABL1 like ALL.

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Il ruolo del next generation sequencing nelle leucemie acute

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  1. 12 aprile 2013 Bologna Il ruolo del next generation sequencing nelle leucemie acute Ilaria Iacobucci Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Università di Bologna, Bologna

  2. Genetic characterization of BCR-ABL1 like ALL Novel rearrangements, copy number alterations, and sequence mutations constitutively activating kinase signaling and dysregulating cytokine receptor signaling. Sample ID Rearrangement Key Lesions PAKTAL STRN3-JAK2 IKZF1 del and p.Leu117fs PAKKCA EBF1-PDGFRBIKZF1 (IK6); EBF1 del; PAX5 inv; CDKN2A/CDKN2B del PAKVKK NUP214-ABL1IKZF1 p.Ser402fs; PAX5 del; CDKN2A/CDKN2B del PALIBN IGH@-EPORIKZF1 e1-5 del; CDKN2A/CDKN2B del PAKYE BCR-JAK2IKZF1 (IK6); EBF1 del; PAX5 del and p.Gly24Arg; CDKN2A/CDKN2B del AMDRM IGH@-CRLF2JAK2 p.Ile682_Arg683insGlyPro; IKZF1 del e1-e6; EBF1 del; PAX5 p.Val319fs; CDKN2A/CDKN2B del PAKKXB IGH@-CRLF2IKZF1 (IK6); CDKN2A/CDKN2B del; FLT3 p.Asn609ins23aa PAKHZT IGH@-CRLF2JAK2 p.Arg867Gln; CDKN2A/CDKN2B del PANNGL PAX5-JAK2IKZF1 del PANSFD ETV6-ABL1IKZF1 (IK6); PAX5 del; CDKN2A/CDKN2B del PANEHF RCSD1-ABL1N/A SJBALL085 NUP214-ABL1IKZF1 (IK6) and p.Ala79fs SJBALL010 RANBP2-ABL1PAX5 del Roberts KG et al. Cancer Cell, 2012

  3. Genetic characterization of hypodiploid ALL Nearhaploid Low hypodiploidy • Receptor tyrosine kinase signaling • and Ras signaling (71%) • Focal deletions of a histone gene cluster at 6p22 (19.1%) • IKZF3 encoding AIOLOS (13%) • TP53 (91.2%) • IKZF2 encoding HELIOS (53%) • RB1 (41%) Li- Fraumeni associatedmutations Nature Genetics 45, 242–252 (2013)

  4. Genetic characterization of BCR-ABL1 positive ALL 5 validated novel missense mutations in BCR-ABL1-positive ALL

  5. Genetic characterization of T-ALL Next Generation Sequencing in T-ALL X chromosometargetedsequencing Wholegenome Wholeexome Wholeexome 12 ETP ALL 67 T-ALL 5 T-ALL 12 male T-ALL cases Activating mutations in genes regulating cytokine receptor and RAS signalling (67% ); inactivating lesions disrupting haematopoietic development (58%); and histone-modifying genes (48%). Mutations of CNOT3 7.9% adult T-ALLs; mutations affecting the ribosomal proteins RPL5 and RPL10 in 9.8% pediatric T-ALLs. Inactivating mutations and deletions in the X-linked plant homeodomain finger 6 (PHF6) gene in 16% of pediatric and 38% of adult primary T-ALL sample. Mutations in NT5C2, which encodes a 5′-nucleotidase enzyme that is responsible for the inactivation of nucleoside-analog chemotherapy drugs. Vlierberghe P, Nat Genet. 2010 Zhang G, et al. Nature 2012 De Keersmaecker K. Nature Genetics, 2013 Tsoneva G. Nature Medicne, 2013

  6. Minimal residualdiseasemonitoring and NGS in ALL Minimal residualdiseasemonitoring and NGS in ALL Deep-sequencing approach for minimal residual disease detection in acute lymphoblastic leukemia Faham M et al. Blood 2012;120:5173-5180 High-Throughput Sequencing Detects Minimal Residual Disease in Acute T Lymphoblastic Leukemia Wu D et al. Sci TranslMed 2012

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