SNP Array Analysis in Acute Myeloid Leukemia Reveals Frequent and Recurrent Acquired Genetic Alterations Linked to Prognosis: a Study of the ALFA Group

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2533-2533
Author(s):  
Olivier Nibourel ◽  
Christophe Roumier ◽  
Samuel Quentin ◽  
Sandrine Geffroy ◽  
Antonio Alberdi ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Snp Array ◽  
Genetic Alterations ◽  
Array Analysis ◽  
Genetic Abnormalities ◽  
Snp Array Analysis ◽  
Conventional Cytogenetics ◽  
Disease Free ◽  
Gene Alterations ◽  
Acute Myeloid

Abstract Abstract 2533 Acute myeloid leukemia (AML) is a heterogeneous disease because of different leukemogenic mechanisms and variable response to antileukemic treatment. In addition to age and leukocytosis at diagnosis, cytogenetic abnormalities are key factors to assess prognosis. Several gene alterations such as those involving CEBPa, NPM1 and FTL3 have been identified and have improved the classification of AML. However, variability remains and cannot be completely explained. In this study, we performed SNP array analysis on a cohort of 128 AML patients in order to identify new genetic alterations and potential new candidate genes involved in leukemogenesis or disease progression. Patients were classified according to MRC cytogenetics (26 favourable; 77 intermediates, 15 adverse, 10 no informative caryotype). Patients were aged from 11 to 65 years and distributed across all French-American-British (FAB) classes except M3 (8 M0, 25 M1, 38 M2, 26 M4 and 11 M4Eo, 12 M5, 2 M6), Paired DNA was extracted from bone marrow aspirates obtained at diagnosis and after achieving complete remission (CR), and analyzed using Affymetrix Genome-Wide Human SNP Array 6.0 to distinguish acquired from constitutional genetic abnormalities. Copy number variations (CNA) were validated on a custom Agilent microarray (Human Genome CGH Microarray 105k). Data were analyzed using Affymetrix' Genotyping Console 3.0.2, Agilent's GeneSpring GX. Statistical analyses were executed using R version 12.1. The Cox proportional hazard regression model was used to relate genetic abnormalities to treatment outcome, with karyotype included as the second covariate. Time was censored at transplantation date if bone marrow transplantation was performed. We found 210 genomic abnormalities in 74 patients: 197 CNA and 13 copy neutral losses of heterozygosity (uniparental disomy or UPD), resulting in 1.6 abnormalities on average per patient (range 0 to 17). Among CNA, deletions were more frequent than gains (130 vs. 66). CNA spanned from 8kb to 191MB (median of gains 24MB, median of losses 2MB). 116 of them had not been detected by conventional cytogenetics. UPD spanned from 23MB to 150MB (median, 33 MB). Abnormalities were located over all chromosomes except for chromosome14 and were particularly frequent on chromosomes 2, 7, 11, 16, 17, and 21 (54% of all abnormalities). We defined 72 minimal common regions which were altered in at least 2 patients. Among the 43 common regions shorter than 5Mb, 16 contain at least one gene reported in AML or cancer. CNA and UPD were distributed across all FAB subtypes. Of note, 7 of 8 patients with AML M0 had 1 or more abnormalities. Among the 74 patients with CNA or UPD, 36 had an intermediate caryotype. We found no significant association of number of abnormalities with known gene alterations known to influence prognosis (i.e., CEBPa, FLT3itd or NPM). As expected, there were significantly more alterations in patients with a favourable or adverse caryotype (P=0.0045, Fisher's exact test). Furthermore, the number of genetic abnormalities was significantly associated to disease-free and to overall survival (P=0.010 and 0.0016, respectively). This remained significant in a multivariate analysis including karyotype (P=0.046 and 0.01, respectively) CNA or UPD was detected in 56% of AML patients who achieved remission of these 45% have intermediate cytogenetics. We identified 43 minimal common regions shorter than 5MB, which were altered in at least 2 patients and 37% of these regions involve genes previously reported in AML or cancer. Increased genomic alterations were significantly associated with favorable and adverse cytogenetics and with disease-free and overall survival. Prognostic significance of number of abnormalities remains significant after adjustment for cytogenetics. DNA SNP array analysis may be useful to better define prognostic subgroups in addition to conventional cytogenetics and may identify candidate genes implicated in leukemogenesis or disease progression. Disclosures: No relevant conflicts of interest to declare.

SNP Array Analysis Reveals Copy Number Alterations and Uniparental Disomy in Mantle Cell Lymphomas at High Resolution.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1585-1585
Author(s):  
Elena M. Hartmann ◽  
Itziar Salaverria ◽  
Silvia Bea ◽  
Andreas Zettl ◽  
Pedro Jares ◽  
...  
Keyword(s):  
High Resolution ◽  
Cell Lines ◽  
Copy Number ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Genetic Alterations ◽  
Array Analysis ◽  
Snp Array Analysis ◽  
Copy Number Changes ◽  
500K Array

Abstract Mantle Cell Lymphoma (MCL) is an aggressive B-Cell Non Hodgkin Lymphoma which is genetically characterized by the translocation t(11;14). This translocation leads to juxtaposition of the Cyclin D1 gene and the IgH locus, resulting in constitutive overexpression of Cyclin D1 and consecutive cell cycle dysregulation. Apart from this typical structural genetic alteration, several studies using conventional or array-based comparative genomic hybridization (CGH) reported a high number of secondary numerical genetic alterations contributing to MCL lymphomagenesis and influencing the clinical behavior. Increasingly, there is evidence that loss of heterozygosity (LOH) without copy number changes (e.g. caused by mitotic recombination between the chromosomal homologues, also referred to as acquired (partial) uniparental disomy (a(p)UPD), is an important alternative mechanism for tumor suppressor gene inactivation. However, this phenomenon is undetectable by CGH techniques. Single Nucleotide Polymorphism (SNP) based arrays allow - in addition to high resolution copy number (CN) analyses and SNP genotyping - in the same experiment the analysis of loss of heterozygosity (LOH) events and hereby enable the detection of copy neutral LOH. We analyzed the 3 t(11;14)-positive MCL cell lines Granta 519, HBL-2 and JVM-2 and 5 primary tumor specimens from untreated MCL patients with both the Affymetrix GeneChip®Human Mapping 100K and 500K array sets. In the 3 cell lines, we found an excellent agreement between the copy number changes obtained by SNP array analysis and previously published array CGH results. Extending published results (Nielaender et al., Leukemia 2006), we found regions of pUPD in all 3 MCL cell lines, which often affected regions reported as commonly deleted in MCL. Intriguingly, HBL-2 that is characterized by relatively few chromosomal losses, carries an increased number of large regions showing copy neutral LOH. Furthermore, we compared the results obtained by the 100K and 500K mapping array sets from 5 primary MCL tumor specimens with previously published conventional CGH data. All cases showed genetic alterations in both conventional CGH and SNP array analysis. The total number of copy number alterations detected by conventional CGH was 35, including 23 losses, 10 gains and 2 amplifications. The total number of CN alterations detected by the mapping 100K and 500K array sets was 81 (50 losses, 26 gains and 5 amplifications) and 82 (50 losses, 27 gains and 5 amplifications), respectively. We found an excellent agreement in the large CN alterations detected by conventional CGH and both SNP array platforms. Furthermore, we identified >40 mostly small CN alterations that have not been detected by conventional CGH (median size <5MB for losses and <3Mb for gains). The CN alterations detected by the 100k and the 500K array sets were highly identical. Importantly, we discovered regions of partial UPD in 4 of the 5 MCL cases (size range from around 2Mb up to a single region >40Mb). In conclusion, the results demonstrate the capability of SNP array analysis for identifying CN alterations and partial UPD at high resolution in MCL cell lines as well as in primary tumor samples.

High Density SNP Array Analysis of Tyrosine Kinase Inhibitor (TKI) Resistant Chronic Myeloid Leukemia (CML) Shows Secondary Genomic Alterations

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3182-3182
Author(s):  
Daniel Nowak ◽  
Norihiko Kawamata ◽  
Tadayuki Akagi ◽  
Ryoko Okamoto ◽  
Nils Thoennissen ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Copy Number ◽  
Myeloid Leukemia ◽  
Snp Array ◽  
High Density ◽  
Array Analysis ◽  
Snp Arrays ◽  
Tki Resistance ◽  
Snp Array Analysis

Abstract Despite the success story of tyrosine kinase inhibitors (TKIs) for the treatment of Chronic Myeloid Leukemia (CML), patients can develop resistances against the drugs. The main known causes for resistance are mutations or over-expression of the BCR/ABL fusion protein, reduced bioavailability of the drugs and activation of compensatory molecular pathways. It is hypothesized that during disease progression, genomic instability of CML cells increases, which may lead to new genomic lesions harboring additional mechanisms of resistance. In this context, we studied genomic DNA profiles of 32 Imatinib resistant CML patients with high density 250K SNP arrays (Affymetrix). Molecular allelokaryotyping for allele specific copy number and loss of heterozygosity analysis was performed with the CNAG software. Single DNA samples from 27 patients were extracted after they had acquired resistance to Imatinib or alternative TKIs such as Nilotinib or Dasatinib. DNA from 12 patients could be analyzed in sequential samples from the initial diagnosis timepoint and a second timepoint upon the emergence of TKI resistance. All patients were positive for BCR/ABL by PCR and FISH. 10 relapse patient samples had known BCR/ABL mutations of which two were T315I mutations. High density allelokaryotyping confirmed pre-existent data on unbalanced translocations, amplifications and deletions from routine cytogenetics: 5 samples displayed a genomic duplication of the BCR/ABL fusion gene, 4 samples had trisomy 8, 1 sample showed deletion of chromosome 17p, 1 sample had heterozygous deletion of chromosome 9. Apart from this, SNP array analysis revealed numerous new submicroscopic genomic lesions. After exclusion of genomic copy number polymorphisms (CNPs) by comparison to recorded CNPs in the UCSC Genome Browser (http://genome.ucsc.edu/) the following results were obtained: Two patients displayed common heterozygous microdeletions of the reciprocal ABL/BCR fusion product. Furthermore, single samples displayed heterozygous micro-deletions on chromosomes 1, 2, 10, 12, 15, 17, and 22 or microduplications on chromosomes 2,3,6, 8, 9, 11, 12, 14, 15, 22. The affected regions contained potentially interesting genes in respect to resistance to therapy such as tumor suppressor candidate MBP-1, apoptosis related protein RERE, metastasis associated gene MTA3, nuclear body associated gene SP100, alpha-T-catenin (CTNNA3), Cbl-interacting protein Sts-1 and the DNA repair associated gene RAD51. As a new genomic alteration in CML, we detected acquired uniparental disomy (UPD) in 5 samples with a common site of UPD on chromosome 19q in 2 patients. In conclusion, in 14 out of 39 TKI resistant cases, high density SNP arrays enabled us to identify submicroscopic copy number lesions and regions of UPD containing promising candidate genes, which merit further research as sites conferring TKI resistance.

The Genotype Consisting of Complex Karyotype and TP53 Gene Mutation Is Specific to Acute Myeloid Leukemia with Multilineage Dysplasia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2507-2507
Author(s):  
Yuichi Ishikawa ◽  
Hitoshi Kiyoi ◽  
Akane Tsujimura ◽  
Yasushi Miyazaki ◽  
Masao Tomonaga ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Who Classification ◽  
Tp53 Mutation ◽  
Genetic Alterations ◽  
Chromosome 17 ◽  
Complex Karyotype ◽  
Genetic Abnormalities ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is a heterogeneous disorder of hematopoietic progenitor cells. The World Health Organization (WHO) classification of the myeloid neoplasm incorporates genetic, immunophenotypic, biologic and clinical features. Although the WHO classification recognizes several chromosomal translocations they are frequently seen in AML patients, for categorizing the AML with recurrent genetic abnormalities, a number of other genetic alterations such as point mutations and gene rearrangements have not been included. To date, several genetic alterations, which are involved in the pathogenesis of AML and associated with prognosis of patients, have been documented. Therefore, it is required to establish the detailed classification of AML according to the genetic status. In this study, we comprehensively analyzed the genetic alterations and in de nove AML patients and investigated the association with mutational status, cytogenetic status and clinical features in comparison with the WHO classification. The study population included 144 newly diagnosed de nove AML patients consisting of 38 recurrent genetic abnormalities (RGA), 34 multilineage dysplasia (MLD) and 72 not otherwise categorized (NOC) according to WHO subcategories. Bone marrow samples were obtained from the patients after obtaining informed consent for banking and molecular analyses. Mutations in FLT3, cKIT, NPM1, N-RAS, TP53, C/EBPA, AML1, WT1 and MLL/PTD were analyzed as previously described. In consistent with previous reports, FLT3 (24%), cKIT (5%), NPM1 (20%), N-RAS (8%), C/EBPA (12%), AML1 (2%), MLL-PTD (9%), WT1 (3%) and TP53 (8%) mutations were frequently observed. No significantly different distribution was found in the prevalence of FLT3, N-RAS, C/EBPA, AML1 and MLL-PTD mutations among the WHO categories. However, the skewed prevalence was found in cKIT, NPM1 and TP53 mutations: cKIT mutation was frequently found in AML-RGA, NPM1 mutation was not found in AML-RGA, and TP53 mutation was preferentially found in AML-MLD. N-RAS, C/EBPA, AML1 and WT1 mutations were not identified in AML-RGA, though their distributions were not statistically significant among the WHO categories. It is notable that 9 of 12 (75%) patients who have TP53 mutation are categorized in AML with MLD and 8 of the 9 have complex-karyotype. Importantly, 8 of 9 (88.9%) showed complex karyotype, and 5 of them deleted chromosome 17. In this study, we found 2 additional patients harboring TP53 mutation in the other categories, while they did not show the complex karyotype and chromosome 17 abnormality. Furthermore, complex karyotype was found in 14 of the 144 entire AML patients, while 10 of them were categorized in AML-MLD. The remaining 4 patients were categorized in AML-NOC. Three of them showed del(17) or del(17p), though TP53 mutation was not identified. The genotype consisting of complex karyotype and TP53 mutation was, therefore, specifically found in AML-MLD. Thus TP53 mutation and complex-karyotype AML are significantly correlated and associated with the presence of multi-lineage dysplasia (P= .000 and P= .000, respectively). Moreover, these patients have significantly inferior induction rate and overall survival in AML with MLD. These results suggest that TP53 mutation and complex-karyotype AML distinguish a disease entity in AML with MLD.

scholarly journals Regions of acquired uniparental disomy at diagnosis of follicular lymphoma are associated with both overall survival and risk of transformation

Blood ◽  
2009 ◽  
Vol 113 (10) ◽  
pp. 2298-2301 ◽  
Author(s):  
Derville O'Shea ◽  
Ciarán O'Riain ◽  
Manu Gupta ◽  
Rachel Waters ◽  
Youwen Yang ◽  
...  
Keyword(s):  
Overall Survival ◽  
Multivariate Analysis ◽  
Follicular Lymphoma ◽  
Snp Array ◽  
Uniparental Disomy ◽  
Progression Free Survival ◽  
Array Analysis ◽  
Free Survival ◽  
Genetic Abnormalities ◽  
Snp Array Analysis

Abstract Acquired homozygosity in the form of segmental acquired uniparental disomy (aUPD) has been described in follicular lymphoma (FL) and is usually due to mitotic recombination. SNP array analysis was performed with the use of the Affymetrix 10K 2.0 Gene-chip array on DNA from 185 diagnostic FL patients to assess the prognostic relevance of aUPD. Genetic abnormalities were detected in 118 (65%) of 182 patients. Number of abnormalities was predictive of outcome; more than 3 abnormalities was associated with inferior overall survival (OS; P < .03). Sites of recurrent aUPD were detected on 6p (n = 25), 16p (n = 22), 12q (n = 17), 1p36 (n = 14), 10q (n = 8), and 6q (n = 8). On multivariate analysis aUPD on 1p36 correlated with shorter OS (P = .05). aUPD on 16p was predictive of transformation (P = .03) and correlated with poorer progression-free survival (P = .02). aUPD is frequent at diagnosis of FL and affects probability of disease transformation and clinical outcome.

scholarly journals Mutations in epigenetic modifiers in the pathogenesis and therapy of acute myeloid leukemia

Blood ◽  
2013 ◽  
Vol 121 (18) ◽  
pp. 3563-3572 ◽  
Author(s):  
Omar Abdel-Wahab ◽  
Ross L. Levine
Keyword(s):  
Acute Myeloid Leukemia ◽  
Posttranslational Modifications ◽  
Myeloid Leukemia ◽  
Somatic Mutations ◽  
Genetic Alterations ◽  
Loss Of Function ◽  
Epigenetic Modifiers ◽  
Genetic Abnormalities ◽  
Acute Myeloid

Abstract Recent studies of the spectrum of somatic genetic alterations in acute myeloid leukemia (AML) have identified frequent somatic mutations in genes that encode proteins important in the epigenetic regulation of gene transcription. This includes proteins involved in the modification of DNA cytosine residues and enzymes which catalyze posttranslational modifications of histones. Here we describe the clinical, biological, and therapeutic relevance of mutations in epigenetic regulators in AML. In particular, we focus on the role of loss-of-function mutations in TET2, gain-of-function mutations in IDH1 and IDH2, and loss-of-function mutations in ASXL1 and mutations of unclear impact in DNMT3A in AML pathogenesis and therapy. Multiple studies have consistently identified that mutations in these genes have prognostic relevance, particularly in intermediate-risk AML patients, arguing for inclusion of mutational testing of these genetic abnormalities in routine clinical practice. Moreover, biochemical, biological, and epigenomic analyses of the effects of these mutations have informed the development of novel therapies which target pathways deregulated by these mutations. Our understanding of the effects of these mutations on hematopoiesis and potential for therapeutic targeting of specific AML subsets is also reviewed here.

Genome-Wide 500K SNP Array Analyses Reveal High Frequencies of Cryptic Genetic Abnormalities and Identify Recurrent Microdeletions Targeting Novel Genes in Adult Acute Lymphoblastic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 458-458
Author(s):  
Kajsa Paulsson ◽  
Jean-Baptiste Cazier ◽  
Jane Stevens ◽  
Tracy Chaplin ◽  
Finlay MacDougall ◽  
...  
Keyword(s):  
Copy Number ◽  
Prognostic Markers ◽  
Lymphoblastic Leukemia ◽  
Snp Array ◽  
Array Analysis ◽  
High Frequencies ◽  
Genome Wide ◽  
Genetic Abnormalities ◽  
Adult Acute Lymphoblastic Leukemia ◽  
Snp Array Analysis

Abstract The long-term disease-free survival rate of adult acute lymphoblastic leukemia (ALL) patients remains less than 40%, in contrast to pediatric cases where it approaches 80%. Furthermore, whereas genetic abnormalities are widely used in childhood ALL for assigning patients to prognostic risk groups, their use in adult ALL is generally restricted to the presence or absence of the t(9;22)/[BCR-ABL1]. Novel prognostic markers, allowing better treatment stratification, and new treatment targets are therefore much needed. We have investigated diagnostic samples from 45 adult ALL cases using genome-wide, high-resolution single nucleotide polymorphism (SNP) array analysis with the Affymetrix 10K, 250K Nsp, and 250K Sty chips, in total including more than 500,000 SNPs with a median inter-marker distance of <2.5 kb. This method, which has not previously been applied to adult ALL, enables the detection of genetic copy number abnormalities as well as uniparental disomies (UPDs) with a much higher resolution than cytogenetic and molecular genetic techniques. We detected 367 genetic abnormalities not corresponding to known copy number polymorphisms among the 45 cases. These comprised 94 copy number gains, 211 hemizygous deletions, 47 homozygous deletions, and 15 UPDs. All but three of the patients (93%) displayed one or more anomaly not detectable with standard genetic analyses. Most notably, we found high frequencies of deletions targeting the genes CDKN2A (P16) (21 cases; 47%), PAX5 (15 cases; 33%), IKZF1 (IKAROS) (8 cases; 18%), ETV6 (7 cases; 16%), RB1 (5 cases; 11%), and EBF1 (2 cases; 4.4%). Thirty-two cases (71%) harbored a deletion of at least one of these genes. CDKN2A deletions were homozygous in 17 cases and associated with partial UPDs in 5 cases. PAX5 deletions were always hemizygous and frequently large, including also CDKN2A in all but three patients. Notably, loss of IKZF1 was found in 5 of 10 (50%) t(9;22)/[BCR-ABL1]-positive ALL cases. Reverse transcriptase-PCR for this gene showed that some t(9;22)-positive cases without this deletion expressed a dominant-negative isoform of IKZF1, suggesting that different mechanisms for downregulation of IKZF1 occur and that this gene is frequently targeted in t(9;22)+ ALL. Furthermore, the SNP array analysis revealed novel recurrent deletions targeting the genes DLG2 (4 cases; 8.9%), LDOC1 (3 cases; 6.7%), ERBB4, and CDH13 (2 cases each; 4.4%). In conclusion, using high-resolution SNP arrays we detect a very high frequency of hidden genetic changes in adult ALL cases. Deletions, frequently cryptic, comprised 70% of the found abnormalities, suggesting that microdeletions are a characteristic feature of adult ALL. Most importantly, the analyses revealed recurrent genetic abnormalities in adult ALL targeting novel genes, not previously implicated in leukemogenesis. In addition to giving new insights into the leukemogenic process, these findings are likely to be clinically important, with the possibility of identifying new prognostic markers as well as future treatment targets in adult ALL.

Comprehensive Analysis of Genetic Alterations in Acute Myeloid Leukemia According to the WHO Classification.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4311-4311
Author(s):  
Yuichi Ishikawa ◽  
Hitoshi Kiyoi ◽  
Akane Tsujimura ◽  
Yasusi Miyazaki ◽  
Masao Tomonaga ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Who Classification ◽  
Normal Karyotype ◽  
Genetic Alterations ◽  
P53 Mutation ◽  
Npm1 Mutation ◽  
Multilineage Dysplasia ◽  
Genetic Abnormalities ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of hematopoietic progenitor cells, and is thought to be the consequence of two broad complementation classes of mutations: those that confer a proliferative and/or survival advantage to hematopoietic progenitors, and those that impair hematopoietic differentiation and confer properties of self-renewal. To date, several genetic alterations, which are involved in the pathophysiology of the AML development, have been apparent, and some of them have been disclosed to have an impact on the clinical management. Therefore, it is required to establish the detailed classification of AML according to the genetic status. In this study, we comprehensively analyzed the genetic alterations in AML patients in comparison with the WHO classification. The study population included 115 newly diagnosed AML patients consisting of 25 recurrent genetic abnormalities, 25 multilineage dysplasia, 7 therapy-related and 56 not otherwise categorized WHO subcategories. Bone marrow samples were obtained from the patients after obtaining informed consent for banking and molecular analyses. Mutations in FLT3, cKIT, NPM1, N-RAS, p53, C/EBPa, AML1 and AKT1 genes were analyzed as previously described. In consistent with previous reports, FLT3 (20.9%), NPM1 (14.8%) and C/EBPa (13.0%) mutations were frequently observed, while no AKT1 mutation was found. Furthermore, NPM1 mutation was not found in AML with recurrent genetic abnormalities and C/EBPa mutation was not found in AML with recurrent genetic abnormalities or therapy related. Nine cases have double mutations of FLT3 and NPM1 genes, and 3 have FLT3 and C/EBPa mutations. Of note is that 15 of 25 (60%) AML with multilineage dysplasia cases have at least one mutation in p53, NPM1, C/EBPa, FLT3, N-RAS and AML1 genes and that p53 mutation was selectively found in the cases with complex karyotype. However, 4 AML with multilineage dysplasia cases with normal karyotype did not have any mutations in the analyzed genes. Comprehensive genetic analysis clarifies the detailed molecular base of AML and could make the subdivision of the WHO classification by combining the analysis for clinical impacts. Especially, mutation status in p53, NPM1 and C/EBPa genes seems to be useful for the subdivision of the AML with multilineage dysplasia, which is the most heterogeneous subcategory in the WHO classification.

Chronic Myeloid Leukemia Patients Sensitive and Resistant to Imatinib Treatment Show Different Metabolic Responses.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3379-3379
Author(s):  
Jianyong Li ◽  
Sixuan Qian ◽  
Jiye Aa ◽  
Guangji Wang ◽  
Sujiang Zhang ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Tricarboxylic Acid Cycle ◽  
Snp Array ◽  
Kinase Domain ◽  
Imatinib Treatment ◽  
Array Analysis ◽  
Metabolic Phenotypes ◽  
Abl Kinase ◽  
Snp Array Analysis

Abstract Abstract 3379 Background: The BCR-ABL tyrosine kinase inhibitor imatinib is highly effective for chronic myeloid leukemia (CML). However, some patients gradually develop resistance to imatinib, resulting in therapeutic failure. Metabonomic and genomic profiling of patients' responses to drug interventions can provide novel information about the in vivo metabolism of low-molecular-weight compounds and extend our insight into the mechanism of drug resistance. Based on a multi-platform of high-throughput metabonomics, SNP array analysis, karyotype and mutation of Abl kinase domain, the metabolic phenotypes and genomic polymorphisms of CML patients and their diverse responses to imatinib were characterized. Methods: We identified 26 untreated CML patients (UCML), 33 patients treated with imatinib at daily doses of 300–800 mg, and 18 healthy volunteers. 14 patients were resistant to imatinib. Routine cytogenetic analysis was performed in patients. In the resistant patients, ABL kinase domain mutations were detected. High-quality genomic DNA was processed in accordance with the genomic mapping 250K NspI protocol and hybridized to 250K NspI SNP arrays according to the manufacturer's instructions in 9 patients treated with imatinib. Gas chromatography/time-of-flight mass spectrometry (GC/TOFMS) was utilized for the measurement of the small molecular weight endogenous compounds. The metabolic phenotypes of CML patients, and the responses of CML to imatinib were characterized by means of GC/TOFMS based metabonomic technique. Results: Mutations were detected in only 1 BC patient (L232P, F336L, and C349R). A total of 44 deletions, 2 duplication, and 7 regions of loss of heterozygosity (LOH) were identified by SNP array analysis. In addition to sex chromosome, four of 6 CP RCML patients did not show other abnormal genome. Deletions, duplication and LOH on chromosome 17, 9, 22, 5 and 19 were identified in several important chromosomal regions of BC patients. The untreated CML patients (UCML) showed different metabolic pattern from those of healthy controls, and the discriminatory metabolites suggested the perturbed metabolism of the urea cycle, tricarboxylic acid cycle, lipid metabolism, and amino acid turnover in UCML. Some amino acids, such as glutamate, ornithine, glycine, and pyroglutamate, were found at higher levels in UCML compared with those in HC, which indicates a cellular requirement for a higher turnover of structural proteins. After imatinib treatment, patients sensitive to imatinib (SCML) and patients resistant to imatinib (RCML) had similar metabolic phenotypes to those of healthy controls and UCML, respectively. SCML showed a significant metabolic response to imatinib, with marked restoration of the perturbed metabolism. Most of the metabolites characterizing CML were adjusted to normal levels, including the intermediates of the urea cycle and tricarboxylic acid cycle (TCA). In contrast, neither cytogenetic nor metabonomic analysis indicated any positive response to imatinib in RCML. Taken together, it strongly suggested that metabolic variation between BC and CP patients were closely related to genomic alterations. Conclusion: We report for the first time the associated genetic and metabonomic responses of CML patients to imatinib and show that the perturbed in vivo metabolism of UCML is independent of imatinib treatment in resistant patients. Thus, metabonomics can potentially characterize patients sensitivity or resistance to drug intervention. Disclosures: No relevant conflicts of interest to declare.

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