Diapositiva 1

Il ruolo del next generation sequencing nelle leucemie acute 12 aprile 2013 Bologna Ilaria Iacobucci Dipartimento di Medicina Specialistica, Diagnostica e Sperimentale, Universit di Bologna, Bologna1Genetic characterization of BCR-ABL1 like ALLSample IDRearrangementKey Lesions

PAKTALSTRN3-JAK2IKZF1 del and p.Leu117fs

PAKKCAEBF1-PDGFRBIKZF1 (IK6); EBF1 del; PAX5 inv; CDKN2A/CDKN2B del

PAKVKKNUP214-ABL1IKZF1 p.Ser402fs; PAX5 del; CDKN2A/CDKN2B del

PALIBNIGH@-EPORIKZF1 e1-5 del; CDKN2A/CDKN2B del

PAKYEBCR-JAK2IKZF1 (IK6); EBF1 del; PAX5 del and p.Gly24Arg; CDKN2A/CDKN2B del

AMDRMIGH@-CRLF2JAK2 p.Ile682_Arg683insGlyPro; IKZF1 del e1-e6; EBF1 del; PAX5 p.Val319fs; CDKN2A/CDKN2B del

PAKKXBIGH@-CRLF2IKZF1 (IK6); CDKN2A/CDKN2B del; FLT3 p.Asn609ins23aa

PAKHZTIGH@-CRLF2JAK2 p.Arg867Gln; CDKN2A/CDKN2B del

PANNGLPAX5-JAK2IKZF1 del

PANSFDETV6-ABL1IKZF1 (IK6); PAX5 del; CDKN2A/CDKN2B del

PANEHFRCSD1-ABL1N/A

SJBALL085NUP214-ABL1IKZF1 (IK6) and p.Ala79fs

SJBALL010RANBP2-ABL1PAX5 delNovel rearrangements, copy number alterations, and sequence mutations constitutively activating kinase signaling and dysregulating cytokine receptor signaling.

Roberts KG et al. Cancer Cell, 2012 Genetic characterization of hypodiploid ALLNear haploid Receptor tyrosine kinase signaling and Ras signaling (71%)Focal deletions of a histone gene cluster at 6p22 (19.1%) IKZF3 encoding AIOLOS (13%)

Low hypodiploidy TP53 (91.2%) IKZF2 encoding HELIOS (53%) RB1 (41%)

Nature Genetics 45, 242252 (2013)

Li- Fraumeni associated mutations

5 validated novel missense mutations in BCR-ABL1-positive ALL

Genetic characterization of BCR-ABL1 positive ALLGenetic characterization of T-ALLNext Generation Sequencing in T-ALLWhole genomeX chromosome targeted sequencing12 male T-ALL cases12 ETP ALLInactivating 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.Vlierberghe P, Nat Genet. 2010Activating mutations in genes regulating cytokine receptor and RAS signalling (67% ); inactivating lesions disrupting haematopoietic development (58%); and histone-modifying genes (48%).Zhang G, et al. Nature 2012 Whole exome67 T-ALLMutations of CNOT3 7.9% adult T-ALLs; mutations affecting the ribosomal proteins RPL5 and RPL10 in 9.8% pediatric T-ALLs.De Keersmaecker K. Nature Genetics, 2013 Whole exome5 T-ALLMutations in NT5C2, which encodes a 5-nucleotidase enzyme that is responsible for the inactivation of nucleoside-analog chemotherapy drugs.Tsoneva G. Nature Medicne, 2013 Minimal residual disease monitoring and NGS in ALLDeep-sequencing approach for minimal residual disease detection in acute lymphoblastic leukemiaFaham M et al. Blood 2012;120:5173-5180

High-Throughput Sequencing Detects Minimal ResidualDisease in Acute T Lymphoblastic LeukemiaWu D et al. Sci Transl Med 2012

Minimal residual disease monitoring and NGS in ALL