[Show abstract][Hide abstract] ABSTRACT: The outcomes of Central Nervous System (CNS) relapses in children with acute lymphoblastic leukaemia (ALL) treated in the ALL R3 trial, between January 2003 and March 2011 were analysed. Patients were risk stratified, to receive a matched donor allogeneic transplant or fractionated cranial irradiation with continued treatment for two years. A randomisation of Idarubicin with Mitoxantrone closed in December 2007 in favour of Mitoxantrone. The estimated 3-year progression free survival for combined and isolated CNS disease were 40.6% (25·1, 55·6) and 38.0% (26.2, 49.7) respectively. Univariate analysis showed a significantly better survival for age <10 years, progenitor-B cell disease, good-risk cytogenetics and those receiving Mitoxantrone. Adjusting for these variables (age, time to relapse, cytogenetics, treatment drug and gender) a multivariate analysis, showed a poorer outcome for those with combined CNS relapse (HR 2·64, 95% CI 1·32, 5·31, p = 0·006 for OS). ALL R3 showed an improvement in outcome for CNS relapses treated with Mitoxantrone compared to Idarubicin; a potential benefit for matched donor transplant for those with very early and early isolated-CNS relapses.
PLoS ONE 01/2014; 9(10):e108107. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Childhood BCR-ABL1-positive B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has an unfavorable outcome and is characterized by a high frequency of IKZF1 deletions. The prognostic value of IKZF1 deletions was evaluated in two cohorts of children with BCR-ABL1-positive BCP-ALL, before (pre-TKI) and after introduction of Imatinib (EsPhALL). IKZF1 deletions were found in 126/191 (66%) of the patients. In the pre-TKI cohort, IKZF1-deleted patients had an unfavorable outcome compared to wild-type patients (4-yr DFS 30.0±6.8% versus 57.5±9.4%, p=0.01). In the EsPhALL-cohort, the IKZF1 deletions were associated with an unfavorable prognosis in patients who were stratified by early clinical response in the good-risk arm (4-yr DFS 51.9±8.8% for IKZF1-deleted versus 78.6±13.9% for IKZF1 wild-type; p=0.03), even when treated with Imatinib (4-yr DFS 55.5±9.5% for IKZF1-deleted versus 75.0±21.7% for IKZF1 wild-type; p=0.05). In conclusion, IKZF1 deletions are predictive for a highly unfavorable outcome in children with BCR-ABL1-positive BCP-ALL irrespective the introduction of Imatinib. These results underscore the urgent need for alternative therapy for IKZF1-deleted BCR-ABL1-positive patients. In contrast, good-risk patients with IKZF1 wild-type responded remarkably well to Imatinib-containing regimens, thus providing a rationale to potentially avoid the use of hematopoietic stem cell transplantation in this subset of BCR-ABL1-positive children.
[Show abstract][Hide abstract] ABSTRACT: Glucocorticoids (GCs) are among the most widely prescribed medications in clinical practice. The beneficial effects of GCs in acute lymphoblastic leukemia (ALL) are based on their ability to induce apoptosis, but the underlying transcriptional mechanisms remain poorly defined. Computational modeling has enormous potential in the understanding of biological processes such as apoptosis and the discovery of novel regulatory mechanisms. We here present an integrated analysis of gene expression kinetic profiles using microarrays from GC sensitive and resistant ALL cell lines and patients, including newly generated and previously published data sets available from the Gene Expression Omnibus. By applying time-series clustering analysis in the sensitive ALL CEM-C7-14 cells, we identified 358 differentially regulated genes that we classified into 15 kinetic profiles. We identified GC response element (GRE) sequences in 33 of the upregulated known or potential GC receptor (GR) targets. Comparative study of sensitive and resistant ALL showed distinct gene expression patterns and indicated unexpected similarities between sensitivity-restored and resistant ALL. We found that activator protein 1 (AP-1), Ets related gene (Erg) and GR pathways were differentially regulated in sensitive and resistant ALL. Erg protein levels were substantially higher in CEM-C1-15-resistant cells, c-Jun was significantly induced in sensitive cells, whereas c-Fos was expressed at low levels in both. c-Jun was recruited on the AP-1 site on the Bim promoter, whereas a transient Erg occupancy on the GR promoter was detected. Inhibition of Erg and activation of GR lead to increased apoptosis in both sensitive and resistant ALL. These novel findings significantly advance our understanding of GC sensitivity and can be used to improve therapy of leukemia.Oncogene advance online publication, 6 August 2012; doi:10.1038/onc.2012.321.
[Show abstract][Hide abstract] ABSTRACT: Trials of imatinib have provided evidence of activity in adults with Philadelphia-chromosome-positive acute lymphoblastic leukaemia (ALL), but the drug's role when given with multidrug chemotherapy to children is unknown. This study assesses the safety and efficacy of oral imatinib in association with a Berlin-Frankfurt-Munster intensive chemotherapy regimen and allogeneic stem-cell transplantation for paediatric patients with Philadelphia-chromosome-positive ALL.
Patients aged 1-18 years recruited to national trials of front-line treatment for ALL were eligible if they had t(9;22)(q34;q11). Patients with abnormal renal or hepatic function, or an active systemic infection, were ineligible. Patients were enrolled by ten study groups between 2004 and 2009, and were classified as good risk or poor risk according to early response to induction treatment. Good-risk patients were randomly assigned by a web-based system with permuted blocks (size four) to receive post-induction imatinib with chemotherapy or chemotherapy only in a 1:1 ratio, while all poor-risk patients received post-induction imatinib with chemotherapy. Patients were stratified by study group. The chemotherapy regimen was modelled on a Berlin-Frankfurt-Munster high-risk backbone; all received four post-induction blocks of chemotherapy after which they became eligible for stem-cell transplantation. The primary endpoints were disease-free survival at 4 years in the good-risk group and event-free survival at 4 years in the poor-risk group, analysed by intention to treat and a secondary analysis of patients as treated. The trial is registered with EudraCT (2004-001647-30) and ClinicalTrials.gov, number NCT00287105.
Between Jan 1, 2004, and Dec 31, 2009, we screened 229 patients and enrolled 178: 108 were good risk and 70 poor risk. 46 good-risk patients were assigned to receive imatinib and 44 to receive no imatinib. Median follow-up was 3·1 years (IQR 2·0-4·6). 4-year disease-free survival was 72·9% (95% CI 56·1-84·1) in the good-risk, imatinib group versus 61·7% (45·0-74·7) in the good-risk, no imatinib group (p=0·24). The hazard ratio (HR) for failure, adjusted for minimal residual disease, was 0·63 (0·28-1·41; p=0·26). The as-treated analysis showed 4-year disease-free survival was 75·2% (61·0-84·9) for good-risk patients receiving imatinib and 55·9% (36·1-71·7) for those who did not receive imatinib (p=0·06). 4-year event-free survival for poor-risk patients was 53·5% (40·4-65·0). Serious adverse events were much the same in the good-risk groups, with infections caused by myelosuppression the most common. 16 patients in the good-risk imatinib group versus ten in the good-risk, no imatinib group (p=0·64), and 24 in the poor-risk group, had a serious adverse event.
Our results suggests that imatinib in conjunction with intensive chemotherapy is well tolerated and might be beneficial for treatment of children with Philadelphia-chromosome-positive ALL.
Projet Hospitalier de Recherche Clinique-Cancer (France), Fondazione Tettamanti-De Marchi and Associazione Italiana per la Ricerca sul Cancro (Italy), Novartis Germany, Cancer Research UK, Leukaemia Lymphoma Research, and Central Manchester University Hospitals Foundation Trust.
The Lancet Oncology 08/2012; 13(9):936-45. · 25.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Failure of remission-induction therapy is a rare but highly adverse event in children and adolescents with acute lymphoblastic leukemia (ALL).
We identified induction failure, defined by the persistence of leukemic blasts in blood, bone marrow, or any extramedullary site after 4 to 6 weeks of remission-induction therapy, in 1041 of 44,017 patients (2.4%) 0 to 18 years of age with newly diagnosed ALL who were treated by a total of 14 cooperative study groups between 1985 and 2000. We analyzed the relationships among disease characteristics, treatments administered, and outcomes in these patients.
Patients with induction failure frequently presented with high-risk features, including older age, high leukocyte count, leukemia with a T-cell phenotype, the Philadelphia chromosome, and 11q23 rearrangement. With a median follow-up period of 8.3 years (range, 1.5 to 22.1), the 10-year survival rate (±SE) was estimated at only 32±1%. An age of 10 years or older, T-cell leukemia, the presence of an 11q23 rearrangement, and 25% or more blasts in the bone marrow at the end of induction therapy were associated with a particularly poor outcome. High hyperdiploidy (a modal chromosome number >50) and an age of 1 to 5 years were associated with a favorable outcome in patients with precursor B-cell leukemia. Allogeneic stem-cell transplantation from matched, related donors was associated with improved outcomes in T-cell leukemia. Children younger than 6 years of age with precursor B-cell leukemia and no adverse genetic features had a 10-year survival rate of 72±5% when treated with chemotherapy only.
Pediatric ALL with induction failure is highly heterogeneous. Patients who have T-cell leukemia appear to have a better outcome with allogeneic stem-cell transplantation than with chemotherapy, whereas patients who have precursor B-cell leukemia without other adverse features appear to have a better outcome with chemotherapy. (Funded by Deutsche Krebshilfe and others.).
New England Journal of Medicine 04/2012; 366(15):1371-81. · 54.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although the overall prognosis in childhood acute lymphoblastic leukemia (ALL) is good, outcome after relapse is poor. Recurrence is frequently characterized by the occurrence of disease at extramedullary sites, such as the central nervous system and testes. Subpopulations of blasts able to migrate to such areas may have a survival advantage and give rise to disease recurrence. Gene expression profiling of 85 diagnostic pre-B-ALL bone marrow samples revealed higher 5T4 oncofetal antigen transcript levels in cytogenetic high-risk subgroups of patients (P<0.001). Flow cytometric analysis determined that bone marrow from relapse patients have a significantly higher percentage of 5T4-positive leukemic blasts than healthy donors (P=0.005). The high-risk Sup-B15 pre-B-ALL line showed heterogeneity in 5T4 expression, and the derived, 5T4(+) (Sup5T4) and 5T4(-) (Sup) subline cells, displayed differential spread to the omentum and ovaries following intraperitoneal inoculation of immunocompromised mice. Consistent with this, Sup5T4 compared with Sup cells show increased invasion in vitro concordant with increased LFA-1 and VLA-4 integrin expression, adhesion to extracellular matrix and secretion of matrix metalloproteases (MMP-2/-9). We also show that 5T4-positive Sup-B15 cells are susceptible to 5T4-specific superantigen antibody-dependent cellular toxicity providing support for targeted immunotherapy in high-risk pre-B-ALL.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 01/2012; 26(7):1487-98. · 10.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: For those of us who look after children with acute lymphoblastic leukemia (ALL), these are heady times. Cure rates on current
therapeutic regimens are now approaching 90% [1, 2]. Therapy is almost entirely chemotherapy-based with very few patients
now receiving irradiation . Why then in this group of patients should we be looking for new agents? The obvious one is
that we are reaching the limits of what can be achieved with combination chemotherapy . In a sense we have been lucky.
Almost all of the earliest chemotherapeutic agents proved effective in childhood ALL. Children tolerate combination chemotherapy
better than adults. This has allowed us to gradually intensify therapy in all groups and in particular those at a higher risk
of relapse. This risk-stratified approach to intensification has proven to be highly effective [5–11]. One problem we now
face is the high cost of cure. Treatment-related mortality and morbidity  is almost balancing out the relative risk of
relapse. Allogeneic stem cell transplant (allo-SCT), the ultimate in treatment intensity, cannot cure patients unless disease
burden is first reduced using chemotherapy [13, 14]. Thus, intensification of therapy is unlikely to improve outcome any further.
We therefore need new drugs not only to cure those currently failed by therapy but also to decrease the morbidity of current
treatment. At present most protocols use ten or more drugs over a period of 2–3 years to treat children with ALL. The cost
of treatment and supportive care is prohibitive for countries with restricted resources. This includes the most heavily populated
parts of the world. Thus, the remarkable success rates seen in developed countries are yet to be translated globally .
To provide a solution for all children with ALL we need shorter, cheaper therapeutic strategies. Finally, childhood ALL is
a paradigm for successful cancer therapy. In terms of modern biology, it is one of the most heavily investigated. In a sense,
having resolved the therapeutic dilemma we now have the luxury of dissecting out the mechanisms of cure and resistance. It
is likely that the biological mechanisms that regulate the variations in the therapeutic response and side effects are common
to more than one tumour type. Thus, the mechanisms identified are likely to have wider application in the treatment of cancer.
[Show abstract][Hide abstract] ABSTRACT: B-cell precursor childhood acute lymphoblastic leukemia with ETV6-RUNX1 (TEL-AML1) fusion has an overall good prognosis, but relapses occur, usually after cessation of treatment and occasionally many years later. We have investigated the clonal origins of relapse by comparing the profiles of genomewide copy number alterations at presentation in 21 patients with those in matched relapse (12-119 months). We identified, in total, 159 copy number alterations at presentation and 231 at relapse (excluding Ig/TCR). Deletions of CDKN2A/B or CCNC (6q16.2-3) or both increased from 38% at presentation to 76% in relapse, suggesting that cell-cycle deregulation contributed to emergence of relapse. A novel observation was recurrent gain of chromosome 16 (2 patients at presentation, 4 at relapse) and deletion of plasmocytoma variant translocation 1 in 3 patients. The data indicate that, irrespective of time to relapse, the relapse clone was derived from either a major or minor clone at presentation. Backtracking analysis by FISH identified a minor subclone at diagnosis whose genotype matched that observed in relapse ∼ 10 years later. These data indicate subclonal diversity at diagnosis, providing a variable basis for intraclonal origins of relapse and extended periods (years) of dormancy, possibly by quiescence, for stem cells in ETV6-RUNX1(+) acute lymphoblastic leukemia.
[Show abstract][Hide abstract] ABSTRACT: We developed a murine model of CNS disease to obtain a better understanding of the pathogenesis of CNS involvement in pre-B-cell acute lymphoblastic leukemia (ALL). Semiquantitative proteomic discovery-based approaches identified unique expression of asparaginyl endopeptidase (AEP), intercellular adhesion molecule 1 (ICAM1), and ras-related C3 botulinum toxin substrate 2 (RAC2), among others, in an invasive pre-B-cell line that produced CNS leukemia in NOD-SCID mice. Targeting RAC2 significantly inhibited in vitro invasion and delayed disease onset in mice. Induced expression of RAC2 in cell lines with low/absent expression of AEP and ICAM1 did not result in an invasive phenotype or murine CNS disease. Flow cytometric analysis identified an enriched population of blast cells expressing ICAM1/lymphocyte function associated antigen-1 (LFA-1)/CD70 in the CD10(+)/CD19(+) fraction of bone marrow aspirates obtained from relapsed compared with normal controls and those with primary disease. CD10(+)/CD19(+) fractions obtained from relapsed patients also express RAC2 and give rise to CNS disease in mice. Our data suggest that combinations of processes are involved in the pathogenesis of CNS disease in pre-B-cell ALL, support a model in which CNS disease occurs as a result of external invasion, and suggest that targeting the processes of adhesion and invasion unique to pre-B cells may prevent recurrences within the CNS.
[Show abstract][Hide abstract] ABSTRACT: Using proteins in a therapeutic context often requires engineering to modify functionality and enhance efficacy. We have previously reported that the therapeutic antileukemic protein macromolecule Escherichia coli L-asparaginase is degraded by leukemic lysosomal cysteine proteases. In the present study, we successfully engineered L-asparaginase to resist proteolytic cleavage and at the same time improve activity. We employed a novel combination of mutant sampling using a genetic algorithm in tandem with flexibility studies using molecular dynamics to investigate the impact of lid-loop and mutations on drug activity. Applying these methods, we successfully predicted the more active L-asparaginase mutants N24T and N24A. For the latter, a unique hydrogen bond network contributes to higher activity. Furthermore, interface mutations controlling secondary glutaminase activity demonstrated the importance of this enzymatic activity for drug cytotoxicity. All selected mutants were expressed, purified, and tested for activity and for their ability to form the active tetrameric form. By introducing the N24A and N24A R195S mutations to the drug L-asparaginase, we are a step closer to individualized drug design.
[Show abstract][Hide abstract] ABSTRACT: Although survival of children with acute lymphoblastic leukaemia has improved greatly in the past two decades, the outcome of those who relapse has remained static. We investigated the outcome of children with acute lymphoblastic leukaemia who relapsed on present therapeutic regimens.
This open-label randomised trial was undertaken in 22 centres in the UK and Ireland and nine in Australia and New Zealand. Patients aged 1-18 years with first relapse of acute lymphoblastic leukaemia were stratified into high-risk, intermediate-risk, and standard-risk groups on the basis of duration of first complete remission, site of relapse, and immunophenotype. All patients were allocated to receive either idarubicin or mitoxantrone in induction by stratified concealed randomisation. Neither patients nor those giving interventions were masked. After three blocks of therapy, all high-risk group patients and those from the intermediate group with postinduction high minimal residual disease (≥10(-4) cells) received an allogenic stem-cell transplant. Standard-risk and intermediate-risk patients with postinduction low minimal residual disease (<10(-4) cells) continued chemotherapy. The primary outcome was progression-free survival and the method of analysis was intention-to-treat. Randomisation was stopped in December, 2007 because of differences in progression-free and overall survival between the two groups. This trial is registered, reference number ISCRTN45724312.
Of 239 registered patients, 216 were randomly assigned to either idarubicin (109 analysed) or mitoxantrone (103 analysed). Estimated 3-year progression-free survival was 35·9% (95% CI 25·9-45·9) in the idarubicin group versus 64·6% (54·2-73·2) in the mitoxantrone group (p=0·0004), and 3-year overall survival was 45·2% (34·5-55·3) versus 69·0% (58·5-77·3; p=0·004). Differences in progression-free survival between groups were mainly related to a decrease in disease events (progression, second relapse, disease-related deaths; HR 0·56, 0·34-0·92, p=0·007) rather than an increase in adverse treatment effects (treatment death, second malignancy; HR 0·52, 0·24-1·11, p=0·11).
As compared with idarubicin, mitoxantrone conferred a significant benefit in progression-free and overall survival in children with relapsed acute lymphobastic leukaemia, a potentially useful clinical finding that warrants further investigation.
Cancer Research UK, Leukaemia and Lymphoma Research, Cancer Council NSW, and Sporting Chance Cancer Foundation.
The Lancet 12/2010; 376(9757):2009-17. · 39.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In a previous analysis of 326 children with Philadelphia chromosome (Ph) -positive acute lymphoblastic leukemia (ALL) treated between 1986 and 1996, hematopoietic stem-cell transplantation from HLA-matched related donors, but not from unrelated donors, offered a superior outcome than chemotherapy alone. To evaluate the impact of recent improvements in chemotherapy and transplantation, we performed a similar analysis on patients treated in the following decade.
We analyzed 610 patients with Ph-positive ALL treated between 1995 and 2005 without tyrosine kinase inhibitor therapy. The median follow-up duration was 6.3 years.
Complete remission was achieved in 89% of patients. The 7-year event-free survival and overall survival rates were superior in the present cohort compared with the previous cohort (32.0% ± 2.0% v 25.0% ± 3.0, respectively, P = .007; and 44.9% ± 2.2% v 36.0% ± 3.0%, respectively, P = .017). Compared with chemotherapy alone, transplantation with matched related donors or unrelated donors in first remission (325 patients) showed an advantage with increasing follow-up, suggesting greater protection against late relapses (hazard ratio at 5 years, 0.37; P < .001). In the multivariate Cox regression analysis accounting for treatment (transplantation v no transplantation), age, leukocyte count, and early response had independent impact on treatment outcome.
Clinical outcome of children and adolescents with Ph-positive ALL has improved with advances in transplantation and chemotherapy. Transplantations with matched related donors and unrelated donors were equivalent and offered better disease control compared with chemotherapy alone. Age, leukocyte count, and early treatment response were independent prognostic indicators. The results of this study will serve as a historical reference to evaluate the therapeutic impact of tyrosine kinase inhibitors on the outcome of Ph-positive ALL.
Journal of Clinical Oncology 09/2010; 28(31):4755-61. · 18.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite the success of contemporary treatment protocols in childhood acute lymphoblastic leukaemia (ALL), relapse within the central nervous system (CNS) remains a challenge. To better understand this phenomenon, we have analysed the changes in incidence and pattern of CNS relapses in 5564 children enrolled in four successive Medical Research Council-ALL trials between 1985 and 2001. Changes in the incidence and pattern of CNS relapses were examined and the relationship with patient characteristics was assessed. The factors affecting outcome after relapse were determined. Overall, relapses declined by 49%. Decreases occurred primarily in non-CNS and combined relapses with a progressive shift towards later (> or =30 months from diagnosis) relapses (P<0.0001). Although isolated CNS relapses declined, the proportional incidence and timing of relapse remained unchanged. Age and presenting white blood cell (WBC) count were risk factors for CNS relapse. On multivariate analysis, the time to relapse and the trial period influenced outcomes after relapse. Relapse trends differed within biological subtypes. In ETV6-RUNX1 ALL, relapse patterns mirrored overall trends whereas in high hyperdiploidy (HH) ALL, these seem to have plateaued over the latter two trial periods. Intensive systemic and intrathecal chemotherapy have decreased the overall CNS relapse rates and changed the patterns of recurrence. The heterogeneity of therapeutic response in the biological subtypes suggests room for further optimization using currently available chemotherapy.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 12/2009; 24(2):450-9. · 10.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: l-Asparaginase is a key therapeutic agent for treatment of childhood acute lymphoblastic leukemia (ALL). There is wide individual variation in pharmacokinetics, and little is known about its metabolism. The mechanisms of therapeutic failure with l-asparaginase remain speculative. Here, we now report that 2 lysosomal cysteine proteases present in lymphoblasts are able to degrade l-asparaginase. Cathepsin B (CTSB), which is produced constitutively by normal and leukemic cells, degraded asparaginase produced by Escherichia coli (ASNase) and Erwinia chrysanthemi. Asparaginyl endopeptidase (AEP), which is overexpressed predominantly in high-risk subsets of ALL, specifically degraded ASNase. AEP thereby destroys ASNase activity and may also potentiate antigen processing, leading to allergic reactions. Using AEP-mediated cleavage sequences, we modeled the effects of the protease on ASNase and created a number of recombinant ASNase products. The N24 residue on the flexible active loop was identified as the primary AEP cleavage site. Sole modification at this site rendered ASNase resistant to AEP cleavage and suggested a key role for the flexible active loop in determining ASNase activity. We therefore propose what we believe to be a novel mechanism of drug resistance to ASNase. Our results may help to identify alternative therapeutic strategies with the potential of further improving outcome in childhood ALL.
The Journal of clinical investigation 07/2009; 119(7):1964-73. · 15.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chromosomal abnormalities are important for the classification and risk stratification of patients with acute lymphoblastic leukemia (ALL). However, approximately 30% of childhood and 50% of adult patients lack abnormalities with clinical relevance. Here, we describe the use of array-based comparative genomic hybridization (aCGH) to identify copy number alterations (CNA) in 58 ALL patients. CNA were identified in 83% of cases, and most frequently involved chromosomes 21 (n=42), 9 (n=21), 6 (n=16), 12 (n=11), 15 (n=11), 8 (n=10) and 17 (n=10). Deletions of 6q (del(6q)) were heterogeneous in size, in agreement with previous data, demonstrating the sensitivity of aCGH to measure CNA. Although 9p deletions showed considerable variability in both the extent and location, all encompassed the CDKN2A locus. Six patients showed del(12p), with a common region encompassing the ETV6 gene. Complex CNA were observed involving chromosomes 6 (n=2), 15 (n=2) and 21 (n=11) with multiple regions of loss and gain along each chromosome. Chromosome 21 CNA shared a common region of gain, with associated subtelomeric deletions. Other recurrent findings included dim(13q), dim(16q) and enh(17q). This is the first report of genome-wide detection of CNA in ALL patients using aCGH, and it has demonstrated a higher level of karyotype complexity than anticipated from conventional cytogenetic analysis.
[Show abstract][Hide abstract] ABSTRACT: We have previously identified a unique subtype of acute lymphoblastic leukemia (ALL) associated with a poor outcome and characterized by intrachromosomal amplification of chromosome 21 including the RUNX1 gene (iAMP21). In this study, array-based comparative genomic hybridization (aCGH) (n = 10) detected a common region of amplification (CRA) between 33.192 and 39.796 Mb and a common region of deletion (CRD) between 43.7 and 47 Mb in 100% and 70% of iAMP21 patients, respectively. High-resolution genotypic analysis (n = 3) identified allelic imbalances in the CRA. Supervised gene expression analysis showed a distinct signature for eight patients with iAMP21, with 10% of overexpressed genes located within the CRA. The mean expression of these genes was significantly higher in iAMP21 when compared to other ALL samples (n = 45). Although genomic copy number correlated with overall gene expression levels within areas of loss or gain, there was considerable individual variation. A unique subset of differentially expressed genes, outside the CRA and CRD, were identified when gene expression signatures of iAMP21 were compared to ALL samples with ETV6-RUNX1 fusion (n = 21) or high hyperdiploidy with additional chromosomes 21 (n = 23). From this analysis, LGMN was shown to be overexpressed in patients with iAMP21 (P = 0.0012). Genomic and expression data has further characterized this ALL subtype, demonstrating high levels of 21q instability in these patients leading to proposals for mechanisms underlying this clinical phenotype and plausible alternative treatments.
Proceedings of the National Academy of Sciences 06/2006; 103(21):8167-72. · 9.81 Impact Factor