Distinct gene expression profiles determine molecular treatment response in childhood acute lymphoblastic leukemia

Blood ◽  
2005 ◽  
Vol 105 (2) ◽  
pp. 821-826 ◽  
Author(s):  
Gunnar Cario ◽  
Martin Stanulla ◽  
Bernard M. Fine ◽  
Oliver Teuffel ◽  
Nils v. Neuhoff ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
Treatment Response ◽  
Expression Profiles ◽  
Lymphoblastic Leukemia ◽  
Treatment Resistance ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Childhood All ◽  
Resistance To Chemotherapy ◽  
Intrinsic Feature

AbstractTreatment resistance, as indicated by the presence of high levels of minimal residual disease (MRD) after induction therapy and induction consolidation, is associated with a poor prognosis in childhood acute lymphoblastic leukemia (ALL). We hypothesized that treatment resistance is an intrinsic feature of ALL cells reflected in the gene expression pattern and that resistance to chemotherapy can be predicted before treatment. To test these hypotheses, gene expression signatures of ALL samples with high MRD load were compared with those of samples without measurable MRD during treatment. We identified 54 genes that clearly distinguished resistant from sensitive ALL samples. Genes with low expression in resistant samples were predominantly associated with cell-cycle progression and apoptosis, suggesting that impaired cell proliferation and apoptosis are involved in treatment resistance. Prediction analysis using randomly selected samples as a training set and the remaining samples as a test set revealed an accuracy of 84%. We conclude that resistance to chemotherapy seems at least in part to be an intrinsic feature of ALL cells. Because treatment response could be predicted with high accuracy, gene expression profiling could become a clinically relevant tool for treatment stratification in the early course of childhood ALL.

High Interleukin-15 Expression Characterizes Childhood Acute Lymphoblastic Leukemia With Involvement of the CNS

2007 ◽  
Vol 25 (30) ◽  
pp. 4813-4820 ◽  
Author(s):  
Gunnar Cario ◽  
Shai Izraeli ◽  
Anja Teichert ◽  
Peter Rhein ◽  
Julia Skokowa ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
Expression Profiles ◽  
Lymphoblastic Leukemia ◽  
Gene Expression Profiles ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Cns Involvement ◽  
Childhood All ◽  
Interleukin 15

Purpose Applying current diagnostic methods, overt CNS involvement is a rare event in childhood acute lymphoblastic leukemia (ALL). In contrast, CNS-directed therapy is essential for all patients with ALL because without it, the majority of patients eventually will experience relapse. To approach this discrepancy and to explore potential distinct biologic properties of leukemic cells that migrate into the CNS, we compared gene expression profiles of childhood ALL patients with initial CNS involvement with the profiles of CNS-negative patients. Patients and Methods We evaluated leukemic gene expression profiles from the bone marrow of 17 CNS-positive patients and 26 CNS-negative patients who were frequency matched for risk factors associated with CNS involvement. Results were confirmed by real-time quantitative polymerase chain reaction analysis and validated using independent patient samples. Results Interleukin-15 (IL-15) expression was consistently upregulated in leukemic cells of CNS-positive patients compared with CNS-negative patients. In multivariate analysis, IL-15 expression levels greater than the median were associated with CNS involvement compared with expression equal to or less than the median (odds ratio [OR] = 10.70; 95% CI, 2.95 to 38.81). Diagnostic likelihood ratios for CNS positivity were 0.09 (95% CI, 0.01 to 0.65) for the first and 6.93 (95% CI, 2.55 to 18.83) for the fourth IL-15 expression quartiles. In patients who were CNS negative at diagnosis, IL-15 levels greater than the median were associated with subsequent CNS relapse compared with expression equal to or less than the median (OR = 13.80; 95% CI, 3.38 to 56.31). Conclusion Quantification of leukemic IL-15 expression at diagnosis predicts CNS status and could be a new tool to further tailor CNS-directed therapy in childhood ALL.

Comparative Analysis of Gene Expression Profiles between Diagnosis and Relapse of Childhood Acute Lymphoblastic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2809-2809
Author(s):  
Tomasz Szczepanski ◽  
Dick de Ridder ◽  
Vincent H.J. van der Velden ◽  
Tom Schonewille ◽  
Elisabeth van Wering ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
Expression Profiling ◽  
Expression Profiles ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Gene Expression Profiles ◽  
Detailed Comparison ◽  
Cell Precursor ◽  
Childhood All

Abstract Approximately 30% of childhood acute lymphoblastic leukemia (ALL) patients relapse, which is the most frequent adverse event in this otherwise curable disease. The mechanisms of relapse are largely unknown. Earlier studies indicated that some relapses might originate from subclones with many different biological features compared to the original ALL clones at diagnosis. Therefore, we aimed at detailed comparison of gene expression profiles between diagnosis and relapse of childhood ALL. The study group consisted of 41 children, 27 diagnosed with B-cell precursor ALL (BCP-ALL) and 14 with T-cell precursor ALL (T-ALL). All samples obtained at diagnosis and relapse were subjected to purification using CliniMACS system and enriched to more than 95% of blasts in each sample. RNA isolation and gene expression profiling were performed according to standard procedures using Affymetrix HG-U133+2 set GeneChip arrays (Affymetrix). The samples were also screened at the RNA level for the most common genetic aberrations occurring in ALL such as t(9;22), t(4;11), t(12;21) and TAL1 deletion. The studies at the DNA level involved detailed comparison of immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements between diagnosis and relapse to assess clonal evolution. GeneChip array data were quantile normalized and background was removed using robust multichip analysis. Significance Analysis of Microarrays (SAM) and t-test were applied to find differentially expressed probe sets between diagnosis and relapse using both the paired and unpaired criterion. The p values < 0.05 were considered significant. The paired SAM analysis revealed 388 significantly differentially expressed (SDE) probe sets for BCP-ALL and 10 SDE probe sets for T-ALL. The differences in expression levels were relatively low, generally not exceeding two-fold. SDE gene sets revealed in our study were mainly different from previously published data, which is most probably due to more stringent purification procedures. Using Ingenuity Systems the SDE genes in BCP-ALL could be significantly linked to several networks involved in cell cycle, DNA replication, recombination, and repair, cellular assembly and organization, cellular growth, proliferation and cancer. There were no significant differences in gene expression profiling in smaller immunophenotypic and cytogenetic ALL subgroups as well as in relation to remission duration (early vs. late relapse). Several SDE genes were found when comparing the ALL with stable Ig/TCR configuration and with some clonal evolution (22 probes for T-ALL and 8 probes for BCP-ALL). In conclusion, discrete differences of gene expression profiles between diagnosis and relapse of childhood ALL indicate heterogeneous origin of relapse. Many relapses represent the simple outgrowth of the original clone, while in other cases many different (leukemia-related) relapse mechanisms might be involved.

scholarly journals Genes contributing to minimal residual disease in childhood acute lymphoblastic leukemia: prognostic significance of CASP8AP2

Blood ◽  
2006 ◽  
Vol 108 (3) ◽  
pp. 1050-1057 ◽  
Author(s):  
Christian Flotho ◽  
Elaine Coustan-Smith ◽  
Deqing Pei ◽  
Shotaro Iwamoto ◽  
Guangchun Song ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Expression Profiles ◽  
Lymphoblastic Leukemia ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Remission Induction ◽  
Induction Treatment ◽  
Minimal Residual

Abstract In childhood acute lymphoblastic leukemia (ALL), early response to treatment is a powerful prognostic indicator. To identify genes associated with this response, we analyzed gene expression of diagnostic lymphoblasts from 189 children with ALL and compared the findings with minimal residual disease (MRD) levels on days 19 and 46 of remission induction treatment. After excluding genes associated with genetic subgroups, we identified 17 genes that were significantly associated with MRD. The caspase 8–associated protein 2 (CASP8AP2) gene was studied further because of its reported role in apoptosis and glucocorticoid signaling. In a separate cohort of 99 patients not included in the comparison of gene expression profiles and MRD, low levels of CASP8AP2 expression predicted a lower event-free survival (P = .02) and a higher rate of leukemia relapse (P = .01) and were an independent predictor of outcome. High levels of CASP8AP2 expression were associated with a greater propensity of leukemic lymphoblasts to undergo apoptosis. We conclude that measurement of CASP8AP2 expression at diagnosis offers a means to identify patients whose leukemic cells are highly susceptible to chemotherapy. Therefore, this gene is a strong candidate for inclusion in gene expression arrays specifically designed for leukemia diagnosis.

scholarly journals TEL-AML1 Fusion Transcript in Relapsed Childhood Acute Lymphoblastic Leukemia

Blood ◽  
1998 ◽  
Vol 91 (5) ◽  
pp. 1716-1722 ◽  
Author(s):  
Karlheinz Seeger ◽  
Hans-Peter Adams ◽  
Dirk Buchwald ◽  
Birgit Beyermann ◽  
Bernhard Kremens ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Prognostic Significance ◽  
Philadelphia Chromosome ◽  
Fusion Transcript ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Long Term Results ◽  
Childhood All ◽  
Cryptic Translocation

Abstract The cryptic translocation t(12;21)(p13;q22) has been recently recognized as the most common genetic rearrangement in B-lineage childhood acute lymphoblastic leukemia (ALL). The resulting fusion transcript, termed TEL-AML1, has been associated with an excellent prognosis at initial ALL diagnosis. Hence, we postulated that the incidence of TEL-AML1 fusion should be lower in patients with ALL relapse. To address this assumption and to investigate the prognostic significance of TEL-AML1 expression in relapsed childhood ALL, bone marrow samples of 146 children were analyzed by reverse-transcriptase (RT)-polymerase chain reaction (PCR). All children were treated according to Berlin-Frankfurt-Münster (BFM) ALL relapse trial protocols (ALL-REZ BFM 90-96). Their clinical features and outcome were compared with those of 262 patients who could not be tested due to lack of bone marrow samples. Thirty-two of 146 children with relapsed ALL were TEL-AML1–positive. Four of the negative patients had T-lineage and nine Philadelphia chromosome (Ph1)-positive leukemia. Thus, the incidence ofTEL-AML1 in relapsed Ph1-negative, B-cell precursor ALL is 32 of 133 (24%). The 32 TEL-AML1–positive and 101 negative patients differed significantly with respect to duration of last remission (42.5 v 27 months; P = .0001) and age at initial diagnosis (53.5 v 74 months;P = .0269). At a median follow-up time of 21.5 months, children positive for TEL-AML1 had a significantly (P = .0011) higher probability of event-free survival (EFS; 0.79 v 0.33). The predominant majority of patients had been treated for initial ALL according to German multicenter BFM (108 of 133) or Cooperative ALL study group (CoALL) (19 of 133) frontline protocols. The comparison of tested and not-tested (N = 262) patients showed no significant difference.TEL-AML1 positivity predicted a favorable short-term outcome; long-term results are unknown. Screening for TEL-AML1 should become routine at relapse diagnosis and might be used for therapy stratification in future trials.

scholarly journals Identification and Validation of Novel Reference Genes in Acute Lymphoblastic Leukemia for Droplet Digital PCR

Genes ◽  
2019 ◽  
Vol 10 (5) ◽  
pp. 376 ◽  
Author(s):  
Vanessa Villegas-Ruíz ◽  
Karina Olmos-Valdez ◽  
Kattia Alejandra Castro-López ◽  
Victoria Estefanía Saucedo-Tepanecatl ◽  
Josselen Carina Ramírez-Chiquito ◽  
...  
Keyword(s):  
Gene Expression ◽  
Acute Lymphoblastic Leukemia ◽  
Reference Genes ◽  
Expression Profiles ◽  
Lymphoblastic Leukemia ◽  
Gene Expression Profiles ◽  
Housekeeping Genes ◽  
Digital Pcr ◽  
Droplet Digital Pcr ◽  
Cellular Processes

Droplet digital PCR is the most robust method for absolute nucleic acid quantification. However, RNA is a very versatile molecule and its abundance is tissue-dependent. RNA quantification is dependent on a reference control to estimate the abundance. Additionally, in cancer, many cellular processes are deregulated which consequently affects the gene expression profiles. In this work, we performed microarray data mining of different childhood cancers and healthy controls. We selected four genes that showed no gene expression variations (PSMB6, PGGT1B, UBQLN2 and UQCR2) and four classical reference genes (ACTB, GAPDH, RPL4 and RPS18). Gene expression was validated in 40 acute lymphoblastic leukemia samples by means of droplet digital PCR. We observed that PSMB6, PGGT1B, UBQLN2 and UQCR2 were expressed ~100 times less than ACTB, GAPDH, RPL4 and RPS18. However, we observed excellent correlations among the new reference genes (p < 0.0001). We propose that PSMB6, PGGT1B, UBQLN2 and UQCR2 are housekeeping genes with low expression in childhood cancer.

scholarly journals TEL/AML-1 dimerizes and is associated with a favorable outcome in childhood acute lymphoblastic leukemia

Blood ◽  
1996 ◽  
Vol 88 (11) ◽  
pp. 4252-4258 ◽  
Author(s):  
TW McLean ◽  
S Ringold ◽  
D Neuberg ◽  
K Stegmaier ◽  
R Tantravahi ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Chromosomal Translocation ◽  
Fusion Transcript ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Childhood All ◽  
Polymerase Chain ◽  
B Lineage

Abstract Polymerase chain reaction-based screening of childhood acute lymphoblastic leukemia (ALL) samples showed that a TEL/AML1 fusion transcript was detected in 27% of all cases, representing the most common known gene rearrangement in childhood cancer. The TEL/AML1 fusion results from a t(12;21)(p13;q22) chromosomal translocation, but was undetectable at the routine cytogenetic level. TEL/AML1-positive patients had exclusively B-lineage ALL, and most patients were between the ages of 2 and 9 years at diagnosis. Only 3/89 (3.4%) adult ALL patients were TEL/AML1-positive. Most importantly, TEL/AML1-positive children had a significantly lower rate of relapse compared with TEL/AML1-negative patients (0/22 v 16/54, P = .004). Co- immunoprecipitation experiments demonstrated that TEL/AML-1 formed homodimers in vitro, and heterodimerized with the normal TEL protein when the two proteins were expressed together. The elucidation of the precise mechanism of transformation by TEL/AML1 and the role of TEL/AML1 testing in the treatment of childhood ALL will require additional studies.

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