scholarly journals Acquired genomic copy number aberrations and survival in adult acute myelogenous leukemia

Blood ◽  
2010 ◽  
Vol 116 (23) ◽  
pp. 4958-4967 ◽  
Author(s):  
Brian Parkin ◽  
Harry Erba ◽  
Peter Ouillette ◽  
Diane Roulston ◽  
Anjali Purkayastha ◽  
...  
Keyword(s):  
Loss Of Heterozygosity ◽  
Acute Myelogenous Leukemia ◽  
Copy Number ◽  
Myelogenous Leukemia ◽  
Prognostic Impact ◽  
P53 Mutations ◽  
Risk Of Death ◽  
Genomic Copy Number ◽  
Genomic Copy ◽  
Acute Myelogenous

Abstract Genomic aberrations are of predominant importance to the biology and clinical outcome of patients with acute myelogenous leukemia (AML), and conventional karyotype-based risk classifications are routinely used in clinical decision making in AML. One of the known limitations of cytogenetic analysis is the inability to detect genomic abnormalities less than 5 Mb in size, and it is currently unclear whether overcoming this limitation with high-resolution genomic single-nucleotide polymorphism (SNP) array analysis would be clinically relevant. Furthermore, given the heterogeneity of molecular mechanisms/aberrations that underlie the conventional karyotype-based risk classifications, it is likely that further refinements in genomic risk prognostication can be achieved. In this study, we analyzed flow cytometer–sorted, AML blast-derived, and paired, buccal DNA from 114 previously untreated prospectively enrolled AML patients for acquired genomic copy number changes and loss of heterozygosity using Affymetrix SNP 6.0 arrays, and we correlated genomic lesion load and specific chromosomal abnormalities with patient survival. Using multivariate analyses, we found that having ≥ 2 genomic lesions detected through SNP 6.0 array profiling approximately doubles the risk of death when controlling for age- and karyotype-based risk. Finally, we identified an independent negative prognostic impact of p53 mutations, or p53 mutations and 17p-loss of heterozygosity combined on survival in AML.

Prognostic impact of trisomy 8 cytogenetic abnormality in acute myelogenous leukemia: Analysis of a large cohort (N=2187) of newly diagnosed patients.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7089-7089
Author(s):  
Gautam Borthakur ◽  
Cecilia Ysabel Arana Yi ◽  
Jorge E. Cortes ◽  
Wei Qiao ◽  
Tapan M. Kadia ◽  
...  
Keyword(s):  
Acute Myelogenous Leukemia ◽  
Remission Rate ◽  
Myelogenous Leukemia ◽  
Cancer Center ◽  
Prognostic Impact ◽  
Intermediate Risk ◽  
Newly Diagnosed ◽  
Trisomy 8 ◽  
Acute Myelogenous ◽  
Md Anderson

7089 Background: Trisomy 8 is grouped as intermediate risk in cytogenetic (CG) classifications of acute myelogenous leukemia (AML). In a multi-variate analysis of MRC data, trisomy 8 was associated with worse overall survival (OS). Methods: Between years 1993-2012, 2,187 patients (pts) with newly diagnosed AML presented at MD Anderson Cancer Center and 21 (10%) were with a trisomy 8 CG abnormality. The median age of trisomy 8 pts was 63 years (range, 17-89 years) and 59% were males. Sixty four (30%) had isolated trisomy 8, 45 (21%) had trisomy 8 +≤2 additional cytogenetic abnormalities and 102 (49%) had trisomy 8 + ≥3 additional abnormalities. Thirty three percent of pts with trisomy 8+≤2 additional abnormalities, had secondary AML compared to 21% of diploid CG (p=.007). Mutations in the FLT3 gene was seen in 9% and N or KRAS gene in 8%. Results: The overall remission rate (RR) was 47%, 53% and 43% among pts with trisomy 8 alone, trisomy 8+≤2 and trisomy 8+≥3 abnormalities respectively. Among pts <60 years of age and with trisomy 8 + ≤2 abnormalities, RR was 71% and the same was 77% for pts with diploid CG. For pts ≥ 60 years, the RRs were 26% and 57% respectively. Among pts ≥ 60 years and trisomy 8 with complex CG (≥3 additional abnormalities) the RR was 38% and that for patients with complex (non-trisomy 8) CG was 41%. Patients with trisomy 8 either alone or ≤2 additional abnormalities had a shorter OS (p= .04 and .05 respectively, median 10.8 and 8.6 months vs 16.5 months) compared to those with diploid CG. Event free survival was also shorter among patient with isolated trisomy 8 versus those with diploid CG (p=.008, median 2.9 versus 7.5 months). On the other hand, patients with trisomy 8+≥3 abnormalities had outcomes comparable to non-trisomy 8 CG group. Conclusions: Non-complex CG trisomy 8 is associated with worse clinical outcome in patients with AML than those with diploid CG and its inclusion in intermediate risk group may need reconsideration. The most adverse impact appears to be from lower RR among patients with trisomy 8+≤2 additional abnormalities and ≥60 years of age.

scholarly journals Recurrent expression signatures of cytokines and chemokines are present and are independently prognostic in acute myelogenous leukemia and myelodysplasia

Blood ◽  
2010 ◽  
Vol 116 (20) ◽  
pp. 4251-4261 ◽  
Author(s):  
Steven M. Kornblau ◽  
David McCue ◽  
Neera Singh ◽  
Wenjing Chen ◽  
Zeev Estrov ◽  
...  
Keyword(s):  
Acute Myelogenous Leukemia ◽  
Multivariable Analysis ◽  
Myelogenous Leukemia ◽  
Therapeutic Interventions ◽  
Leukemic Cells ◽  
Prognostic Impact ◽  
Primary Resistance ◽  
Cytokines And Chemokines ◽  
Acute Myelogenous ◽  
Normal Controls

AbstractThe role of circulating cytokines and chemokines (C&Ckine) in activating signal transduction in leukemic cells is incompletely defined. We hypothesized that comprehensive profiling of C&Ckine expression in leukemia would provide greater insight compared with individual analyses. We used multiplex array technology to simultaneously measure the level of 27 C&Ckines in serum from 176 acute myelogenous leukemia (AML) and 114 myelodysplastic syndrome (MDS) patients and 19 normal controls. C&Ckine levels in AML and MDS differed significantly from normal controls (5 higher, 13 lower) but were similar to each other for 24 of 27 analytes, with interleukin-8 and interleukin-13 higher in AML and vascular endothelial growth factor A higher in MDS. Levels did not correlate with age, gender, infection, or blood counts; however, 3 correlated with specific cytognetic abnormalities in AML. Individually, few cytokines had any correlation with response or survival. In newly diagnosed AML, 8 C&Ckine signatures, distinct from the normal control signature, were observed. These signatures had prognostic impact, affecting remission, primary resistance, relapse rates, and overall survival, individually (P = .003) and in multivariable analysis (P = .004). These patterns suggest specific therapeutic interventions to investigate in subsets of AML patients. In conclusion, C&Ckine expression in AML and MDS differs from normal, is similar with one another, and forms recurrent patterns of expression with prognostic relevance.

P102 Proposed loss of heterozygosity of HLA class I region during acute myelogenous leukemia blast crisis

2017 ◽  
Vol 78 ◽  
pp. 128
Author(s):  
Michelle J. Hickey ◽  
Nicole Valenzuela ◽  
Qiuheng Zhang ◽  
Ping Ge Takemura ◽  
Elaine F. Reed ◽  
...  
Keyword(s):  
Loss Of Heterozygosity ◽  
Acute Myelogenous Leukemia ◽  
Blast Crisis ◽  
Hla Class I ◽  
Myelogenous Leukemia ◽  
Class I ◽  
Leukemia Blast ◽  
Acute Myelogenous ◽  
Class I Region

Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis

Blood ◽  
2002 ◽  
Vol 99 (12) ◽  
pp. 4326-4335 ◽  
Author(s):  
Christian Thiede ◽  
Christine Steudel ◽  
Brigitte Mohr ◽  
Markus Schaich ◽  
Ulrike Schäkel ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Acute Myelogenous Leukemia ◽  
Point Mutations ◽  
Disease Free Survival ◽  
Myelogenous Leukemia ◽  
Tyrosine Kinase Domain ◽  
Prognostic Impact ◽  
Constitutive Activation ◽  
Juxtamembrane Region ◽  
Acute Myelogenous

Constitutive activation of the FLT3 receptor tyrosine kinase, either by internal tandem duplication (ITD) of the juxtamembrane region or by point mutations in the second tyrosine kinase domain (TKD), has been described in patients with acute myelogenous leukemia (AML). We analyzed the prevalence and the potential prognostic impact of FLT3 mutations in 979 AML patients. Results were correlated with cytogenetic data and the clinical response. FLT3-ITD mutations were found in 20.4% and FLT3-TKD mutations in 7.7% of the patients. Each mutation was associated with similar clinical characteristics and was more prevalent in patients with normal karyotype. Significantly more FLT3 aberrations were found in patients with FAB M5, and fewer were found in patients with FAB M2 and M6. Although less frequent in patients with cytogenetic aberrations, FLT3-ITDs were found in 13 of 42 patients with t(15;17) and in 9 of 10 patients with t(6;9). The prevalence of the ITD allele on the DNA level was heterogeneous, ranging from faint mutant bands in some patients to predominant mutant bands in others. Based on quantitative analysis, the mutant–wild-type (wt) ratio ranged from 0.03 to 32.56 (median, 0.78). Patients with a high mutant/wt ratio (ie, greater than 0.78) had significantly shorter overall and disease-free survival, whereas survival in patients with ratios below 0.78 did not differ from those without FLT3 aberrations. Multivariate analysis confirmed a high mutant/wt ratio to be a strong independent prognostic factor. Taken together, these data confirm that FLT mutations represent a common alteration in adult AML. Constitutive activation may be associated with monocytoid differentiation. A high mutant/wt ratio in ITD-positive patients appears to have a major impact on the prognostic relevance.

Genome-Wide Analysis of Microdeletions and Identification of NF1 Inactivation in Acute Myelogenous Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 165-165
Author(s):  
Sami Malek ◽  
Peter Ouillette ◽  
Yin Wang ◽  
Yan Liu ◽  
Whitney Wright ◽  
...  
Keyword(s):  
Acute Myelogenous Leukemia ◽  
Copy Number ◽  
Research Funding ◽  
Normal Karyotype ◽  
B Cell Lymphoma ◽  
Myelogenous Leukemia ◽  
Acute Myelogenous ◽  
Copy Number Changes ◽  
Induced Apoptosis ◽  
High Level

Abstract Abstract 165 Genomic aberrations are of dominant importance to the biology and clinical outcome of patients with acute myelogenous leukemia (AML). To further our understanding of such aberrations in AML, we analyzed DNA from highly purified AML blasts and paired buccal cells from 95 patients for subchromosomal copy number changes and allele identities using ultra-high-density Affymetrix SNP 6.0 array-based genomic profiling. A total of 358 somatically acquired copy number changes were detected in 95 AML genomes. We detected 16 losses and 22 gains of entire chromosomes, 285 subchromosomal losses and 35 subchromosomal gains. No recurrent high-level amplifications or recurrent homozygous deletions were identified. Eight of the 34 AML cases (24%) with normal karyotype each had one lesion detected through 6.0 array profiling, all but one of which was less than 4Mb in length. Focusing on microdeletions as potential indicators of the locations of novel tumor suppressor genes or genes with importance to AML biology, we identified 60 deletions that were less than 1 Mb in length and 158 deletions of less than 5 Mb, the vast majority of which were undetectable by conventional cytogenetics. Through fine mapping of microdeletions on 17q, we identified Neurofibromin 1 (NF1) null states due to mutations or absent expression in ∼7% of AML. NF1 mutations were present in the hematopoetic stem cell compartment (CD34+/CD38- cell population) and siRNA-mediated NF1 suppression using recombinant lentiviruses significantly increased colony formation of primary AML blasts in methylcellulose. Further, AML blasts without functional NF1 displayed sensitivity to rapamycin-induced apoptosis, thus identifying a dependence on mTOR signaling for survival. As an additional validation of using microdeletions to guide pathogenetic gene discovery, we identified deletions involving RUNX1, IRF8, Core Binding Factor Beta (CBFB) and Casitas B-cell lymphoma B (CBLB), genes known to be altered in AML. IRF8 expression was found to be absent in ∼30% of all AML but sequencing of all coding exons of IRF8 of 48 AML cases did not disclose somatically acquired mutations. In summary, this comprehensive description of subchromosomal copy number changes and microdeletions in adult AML substantially adds to our knowledge of the pathological anatomy of the AML genome and should inform future searches for novel genes with importance to AML biology. Disclosures: Malek: Cephalon: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Affymetrix: Research Funding. Erba:Lilly: Research Funding; Antisoma: Research Funding; Wyeth: Research Funding; Cephalon: Honoraria, Research Funding; MGI Pharma: Honoraria; Pharmion: Honoraria; Celgene: Honoraria; BMS: Honoraria; Novartis: Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; Gemin-X: Research Funding; Kanisa: Research Funding.

Allelotyping of acute myelogenous leukemia: loss of heterozygosity at 7q31.1 (D7S486) and q33-34 (D7S498, D7S505)

1999 ◽  
Vol 23 (3) ◽  
pp. 307-310 ◽  
Author(s):  
Michiaki Koike ◽  
Taizo Tasaka ◽  
S. Spira ◽  
Nobuyoshi Tsuruoka ◽  
H. Phillip Koeffler
Keyword(s):  
Loss Of Heterozygosity ◽  
Acute Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
Acute Myelogenous

Loss of heterozygosity in childhood de novo acute myelogenous leukemia

Blood ◽  
2001 ◽  
Vol 98 (4) ◽  
pp. 1188-1194 ◽  
Author(s):  
David A. Sweetser ◽  
Chien-Shing Chen ◽  
Adam A. Blomberg ◽  
David A. Flowers ◽  
Patricia C. Galipeau ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Loss Of Heterozygosity ◽  
Acute Myelogenous Leukemia ◽  
Tumor Suppressor Genes ◽  
De Novo ◽  
Myelogenous Leukemia ◽  
Allelic Loss ◽  
Suppressor Genes ◽  
A Genome ◽  
Acute Myelogenous

A genome-wide screening for loss of heterozygosity (LOH), a marker for possible involvement of tumor suppressor genes, was conducted in 53 children with de novo acute myelogenous leukemia (AML). A total of 177 highly polymorphic microsatellite repeat markers were used in locus-specific polymerase chain reactions. This comprehensive allelotyping employed flow-sorted cells from diagnostic samples and whole-genome amplification of DNA from small, highly purified samples. Nineteen regions of allelic loss in 17 patients (32%) were detected on chromosome arms 1q, 3q, 5q, 7q (n = 2), 9q (n = 4), 11p (n = 2), 12p (n = 3), 13q (n = 2), 16q, 19q, and Y. The study revealed a degree of allelic loss underestimated by routine cytogenetic analysis, which failed to detect 9 of these LOH events. There was no evidence of LOH by intragenic markers for p53, Nf1, orCBFA2/AML1. Most lymphocytes lacked the deletions, which were detected only in the leukemic myeloid blast population. Analysis of patients' clinical and biologic characteristics indicated that the presence of LOH was associated with a white blood cell count of 20 × 109/L or higher but was not correlated with a shorter overall survival. The relatively low rate of LOH observed in this study compared with findings in solid tumors and in pediatric acute lymphoblastic leukemia and adult AML suggests that tumor suppressor genes are either infrequently involved in the development of pediatric de novo AML or are inactivated by such means as methylation and point mutations. Additional study is needed to determine whether these regions of LOH harbor tumor suppressor genes and whether specific regions of LOH correlate with clinical characteristics.

Are Disparities in Acute Myelogenous Leukemia Due to Poor Prognostic Factors At Diagnosis? A National Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2061-2061
Author(s):  
Manali I. Patel ◽  
Yifei Ma ◽  
Beverly S. Mitchell ◽  
Kim Rhoads
Keyword(s):  
Ethnic Groups ◽  
Acute Myelogenous Leukemia ◽  
Myelogenous Leukemia ◽  
Age At Diagnosis ◽  
Risk Of Death ◽  
Younger Age ◽  
Acute Myelogenous ◽  
Race Ethnicity ◽  
Multivariable Models ◽  
Racial Ethnic

Abstract Abstract 2061 Background: Disparities in Acute myelogenous leukemia (AML) have been described but not studied extensively in adults. Younger age at diagnosis and cytogenetic profiles of t(8;21) and acute promyelocytic leukemia (APL) subtypes of AML have been associated with improved survival from AML but no studies to date have evaluated these factors by race. The purpose of the current study is to evaluate differences by race/ethnicity in age and select cytogenetic factors at diagnosis. The hypothesis is that disparities for minorities will be explained by older age at diagnosis and lower rates of select favorable cytogenetics. Methods: Patients with AML were identified in the Surveillance Epidemiology End Results (SEER) database during the years 1999–2008. Kaplan-Meier survival curves were generated to predict survival by race/ethnicity, stratified by age. Multivariable Cox proportional hazard models estimated mortality by race with adjustment for age, gender, year of diagnosis, t(8;21) and APL subtypes. Results: A total of 27,252 patients were included in the study. Blacks and Hispanics were diagnosed at younger ages (<61 years) and had higher rates of t(8;21) and APL compared with non-Hispanic Whites (NHW). The overall KM curve demonstrates that NHWs had a worse survival compared to other races/ethnicities. However when KM curves were stratified by age, blacks and Hispanics had worse survival in every age category below age 61. In multivariable models adjusted for age, black patients had an increased risk of death compared to NHWs (HR 1.10 95% CI (1.04–1.16). In multivariable models adjusted for t(8;21) and APL subtypes, there was no attenuation for the disparity. For APL subtype, in particular, there was an increased disparity for blacks (HR 1.11 95% CI (1.05–1.17) and Hispanics (HR 1.05 95% CI (1.01–1.11) compared to NHWs. Conclusions: Despite younger age and higher prevalence of favorable cytogenetics, blacks have worse mortality from AML compared to other racial/ethnic groups. Blacks and Hispanics with the APL subtype have worse mortality compared to other racial/ethnic groups. Future studies should investigate other reasons for disparities among black and Hispanics with acute myelogenous leukemia. Disclosures: No relevant conflicts of interest to declare.

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