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The genomic landscape of hypodiploid acute lymphoblastic leukemia.

ABSTRACT: The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), a subtype of ALL characterized by aneuploidy and poor outcome, is unknown. Genomic profiling of 124 hypodiploid ALL cases, including whole-genome and exome sequencing of 40 cases, identified two subtypes that differ in the severity of aneuploidy, transcriptional profiles and submicroscopic genetic alterations. Near-haploid ALL with 24-31 chromosomes harbor alterations targeting receptor tyrosine kinase signaling and Ras signaling (71%) and the lymphoid transcription factor gene IKZF3 (encoding AIOLOS; 13%). In contrast, low-hypodiploid ALL with 32-39 chromosomes are characterized by alterations in TP53 (91.2%) that are commonly present in nontumor cells, IKZF2 (encoding HELIOS; 53%) and RB1 (41%). Both near-haploid and low-hypodiploid leukemic cells show activation of Ras-signaling and phosphoinositide 3-kinase (PI3K)-signaling pathways and are sensitive to PI3K inhibitors, indicating that these drugs should be explored as a new therapeutic strategy for this aggressive form of leukemia.

SUBMITTER: Holmfeldt L

PROVIDER: S-EPMC3919793 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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The genomic landscape of hypodiploid acute lymphoblastic leukemia.

Holmfeldt Linda L Wei Lei L Diaz-Flores Ernesto E Walsh Michael M Zhang Jinghui J Ding Li L Payne-Turner Debbie D Churchman Michelle M Andersson Anna A Chen Shann-Ching SC McCastlain Kelly K Becksfort Jared J Ma Jing J Wu Gang G Patel Samir N SN Heatley Susan L SL Phillips Letha A LA Song Guangchun G Easton John J Parker Matthew M Chen Xiang X Rusch Michael M Boggs Kristy K Vadodaria Bhavin B Hedlund Erin E Drenberg Christina C Baker Sharyn S Pei Deqing D Cheng Cheng C Huether Robert R Lu Charles C Fulton Robert S RS Fulton Lucinda L LL Tabib Yashodhan Y Dooling David J DJ Ochoa Kerri K Minden Mark M Lewis Ian D ID To L Bik LB Marlton Paula P Roberts Andrew W AW Raca Gordana G Stock Wendy W Neale Geoffrey G Drexler Hans G HG Dickins Ross A RA Ellison David W DW Shurtleff Sheila A SA Pui Ching-Hon CH Ribeiro Raul C RC Devidas Meenakshi M Carroll Andrew J AJ Heerema Nyla A NA Wood Brent B Borowitz Michael J MJ Gastier-Foster Julie M JM Raimondi Susana C SC Mardis Elaine R ER Wilson Richard K RK Downing James R JR Hunger Stephen P SP Loh Mignon L ML Mullighan Charles G CG

Nature genetics 20130120 3

The genetic basis of hypodiploid acute lymphoblastic leukemia (ALL), a subtype of ALL characterized by aneuploidy and poor outcome, is unknown. Genomic profiling of 124 hypodiploid ALL cases, including whole-genome and exome sequencing of 40 cases, identified two subtypes that differ in the severity of aneuploidy, transcriptional profiles and submicroscopic genetic alterations. Near-haploid ALL with 24-31 chromosomes harbor alterations targeting receptor tyrosine kinase signaling and Ras signali ...[more]

PMID: 23334668

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Project description:BackgroundTreatment on risk adapted intensive pediatric protocols has improved outcome for teenagers and young adults (TYA) with T-cell acute lymphoblastic leukemia (T-ALL). Understanding the biology of disease in this age group and the genetic basis of relapse is a key goal as patients with relapsed/refractory disease have poor outcomes with conventional chemotherapy and novel molecular targets are required. This study examines the question of whether TYA T-ALL has a specific biological-molecular profile distinct from pediatric or adult T-ALL.MethodsGenomic characterization was undertaken of a retrospective discovery cohort of 80 patients aged 15-26 years with primary or relapsed T-ALL, using a combination of Genome-Wide Human SNP Array 6.0, targeted gene mutation and promoter methylation analyses. Findings were confirmed by MLPA, real-time quantitative PCR, and FISH. Whole Exome Sequencing was performed in 4 patients with matched presentation and relapse to model clonal evolution. A prevalence analysis was performed on a final data set of 1,792 individual cases to identify genetic lesions with age specific frequency patterns, including 972 pediatric (1-14 years), 439 TYA (15-24 years) and 381 adult (≥25 years) cases. These cases were extracted from 19 publications with comparable genomic data identified through a PubMed search.ResultsGenomic characterization of this large cohort of TYA T-ALL patients identified recurrent isochromosome 7q i(7q) in our discovery cohort (n = 3). Prevalence analysis did not identify any age specific genetic abnormalities. Genomic analysis of 6 pairs of matched presentation - relapsed T-ALL established that all relapses were clonally related to the initial leukemia. Whole exome sequencing analysis revealed recurrent, targetable, mutations disrupting NOTCH, PI3K/AKT/mTOR, FLT3, NRAS as well as drug metabolism pathways.ConclusionsAll genetic aberrations in TYA T-ALL occurred with an incidence similar or intermediate to that reported in the pediatric and adult literature, demonstrating that overall TYA T-ALL exhibits a transitional genomic profile. Analysis of matched presentation - relapse supported the hypothesis that relapse is driven by the Darwinian evolution of sub-clones associated with drug resistance (NT5C2 and TP53 mutations) and re-iterative mutation of known key T-ALL drivers, including NOTCH1.

Dataset Information

The genomic landscape of hypodiploid acute lymphoblastic leukemia.

Publications

The genomic landscape of hypodiploid acute lymphoblastic leukemia.

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