Introduction. Although treatment with tyrosine kinase inhibitors has revolutionized the management of adult patients with BCR-ABL1-positive ALL and significantly improved response rates, relapse is still an expected and early event in the majority of them. It is usually attributed to the emergence of resistant clones with mutations in BCR-ABL1 kinase domain or to BCR-ABL1-independent pathways but many questions remain unresolved about the genetic abnormalities responsible for relapse. Patients and methods. In an attempt to better understand the genetic mechanisms responsible for this phenomenon, we have analyzed matched diagnosis-relapse samples from 20 adult BCR-ABL1-positive ALL patients using high resolution Affymetrix single nucleotide polymorphism (SNP) arrays (GeneChip® Human Mapping 250K NspI, n=15 pairs and Genome-Wide Human SNP 6.0, n=5 pairs). Genetic differences were analyzed in terms of copy number changes and loss of heterozygosity (LOH) events. Patients were enrolled in clinical trials of GIMEMA AL Working Party and treated with imatinib alone or in combination with conventional chemotherapy (40%) or dasatinib as frontline therapy (60%). The median age at diagnosis was 54 years (range 23-74) and the median blast cell count was 97% (range 60-99). The median time to relapse was 27 months (range, 9-104). Results. In 2/20 (10%) patients no genomic differences between diagnosis and relapse samples were found (“stable group”), suggesting that only BCR-ABL1 mutations or extraleukemic factors (e.g., drug distribution, drug metabolism, compliance) contributed to the relapse. In the remaining cases (90%), new acquired copy number alterations (CNAs) were detected at relapse (“unstable group”). Acquired macroscopic alterations (>1.5 MB) were detected in 6 (30%) cases and included gain of chromosome 1q, 16q22, 9q and 22q (regions flanking the ABL and BCR genes), 19p13.3 (ABCA7, APC2, ARID3A) and 11q12.1-11q25; macroscopic losses affected the locus 1p36 in 2 cases. The gene most frequently affected by microscopic CNAs (<1.5 Mb) was the tumor suppressor CDKN2A/B (20%). Other common acquired CNAs included gains of ABC transporter genes, such as ABCC1, ABCC6 (1q41) and BCL8 (15q11); losses affected EBF1 (5q33) and IGLL3 (22q11) genes involved in B-cell development, BTG1 (12q21) involved in cell cycle regulation and CHEK2 (22q12) involved in DNA repair. The majority (92%) of relapse samples harbored at least some of the CNAs present in the matched diagnosis sample, indicating a common clonal origin. Conclusions. Genomic alterations evolving from diagnosis to relapse have been identified demonstrating that a diversity of alterations contributes to relapse and with the most common alterations targeting key regulators of tumor suppression, cell cycle control, and lymphoid/B cell development. Supported by: AIL, AIRC, Fondazione Del Monte di Bologna e Ravenna, FIRB 2006, PRIN 2008, European LeukemiaNet, GIMEMA ONLUS, Ateneo RFO grants, Project of integrated program (PIO), Programma di Ricerca Regione, Università 2007-2009.

FROM DIAGNOSIS TO RELAPSE: AN HIGH-RESOLUTION MOLECULAR ALLELOKARYOTYPING ANALYSIS OF PAIRED DIAGNOSIS-RELAPSE SAMPLES IN BCR-ABL1-POSITIVE ALL INDICATES INVOLVEMENT OF ALTERATIONS TARGETING KEY REGULATORS OF TUMOR SUPPRESSION, CELL CYCLE CONTROL, AND LYMPHOID/B CELL DEVELOPMENT

IACOBUCCI, ILARIA;LONETTI, ANNALISA;Ferrari A;PAPAYANNIDIS, CRISTINA;ABBENANTE, MARIACHIARA;OTTAVIANI, EMANUELA;PAOLINI, STEFANIA;Parisi S;SOVERINI, SIMONA;MARTINELLI, GIOVANNI
2010

Abstract

Introduction. Although treatment with tyrosine kinase inhibitors has revolutionized the management of adult patients with BCR-ABL1-positive ALL and significantly improved response rates, relapse is still an expected and early event in the majority of them. It is usually attributed to the emergence of resistant clones with mutations in BCR-ABL1 kinase domain or to BCR-ABL1-independent pathways but many questions remain unresolved about the genetic abnormalities responsible for relapse. Patients and methods. In an attempt to better understand the genetic mechanisms responsible for this phenomenon, we have analyzed matched diagnosis-relapse samples from 20 adult BCR-ABL1-positive ALL patients using high resolution Affymetrix single nucleotide polymorphism (SNP) arrays (GeneChip® Human Mapping 250K NspI, n=15 pairs and Genome-Wide Human SNP 6.0, n=5 pairs). Genetic differences were analyzed in terms of copy number changes and loss of heterozygosity (LOH) events. Patients were enrolled in clinical trials of GIMEMA AL Working Party and treated with imatinib alone or in combination with conventional chemotherapy (40%) or dasatinib as frontline therapy (60%). The median age at diagnosis was 54 years (range 23-74) and the median blast cell count was 97% (range 60-99). The median time to relapse was 27 months (range, 9-104). Results. In 2/20 (10%) patients no genomic differences between diagnosis and relapse samples were found (“stable group”), suggesting that only BCR-ABL1 mutations or extraleukemic factors (e.g., drug distribution, drug metabolism, compliance) contributed to the relapse. In the remaining cases (90%), new acquired copy number alterations (CNAs) were detected at relapse (“unstable group”). Acquired macroscopic alterations (>1.5 MB) were detected in 6 (30%) cases and included gain of chromosome 1q, 16q22, 9q and 22q (regions flanking the ABL and BCR genes), 19p13.3 (ABCA7, APC2, ARID3A) and 11q12.1-11q25; macroscopic losses affected the locus 1p36 in 2 cases. The gene most frequently affected by microscopic CNAs (<1.5 Mb) was the tumor suppressor CDKN2A/B (20%). Other common acquired CNAs included gains of ABC transporter genes, such as ABCC1, ABCC6 (1q41) and BCL8 (15q11); losses affected EBF1 (5q33) and IGLL3 (22q11) genes involved in B-cell development, BTG1 (12q21) involved in cell cycle regulation and CHEK2 (22q12) involved in DNA repair. The majority (92%) of relapse samples harbored at least some of the CNAs present in the matched diagnosis sample, indicating a common clonal origin. Conclusions. Genomic alterations evolving from diagnosis to relapse have been identified demonstrating that a diversity of alterations contributes to relapse and with the most common alterations targeting key regulators of tumor suppression, cell cycle control, and lymphoid/B cell development. Supported by: AIL, AIRC, Fondazione Del Monte di Bologna e Ravenna, FIRB 2006, PRIN 2008, European LeukemiaNet, GIMEMA ONLUS, Ateneo RFO grants, Project of integrated program (PIO), Programma di Ricerca Regione, Università 2007-2009.
2010
S3
S29
S29
Iacobucci I; Lonetti A; Ferrari A; Papayannidis C; Abbenante M; Ottaviani E; Paolini S; Guadagnuolo V; Parisi S; Vitale A; Vignetti M; Cilloni D; Pane F; Soverini S; Foà R; Baccarani M; Martinelli G
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11585/154765
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