The expression of 70 apoptosis genes in relation to lineage, genetic subtype, cellular drug resistance, and outcome in childhood acute lymphoblastic leukemia

Holleman, Amy; Boer, Monique L. den; Menezes, Renée X. de; Cheok, Meyling; Cheng, Cheng; Kazemier, Karin M.; Janka‐Schaub, Gritta; Göbel, U.; Graubner, Ulrike; Evans, William E.; Pieters, Rob

doi:10.1182/blood-2005-07-2930

Cited by 127 publications

(101 citation statements)

References 68 publications

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“…Genes significantly correlated with both MPRED and DEX resistance included DCK (deoxycytidine kinase; downregulated), CYP3A4 (downregulated), CCND1 (Cyclin D1; upregulated) and the multidrug transporter ABCC9 (upregulated). In contrast to previous work reporting an association between prednisolone sensitivity and expression of MCL1 or DAPK1 in ALL patient specimens (Holleman et al, 2005;Wei et al, 2006), we found no correlation of these genes with GC resistance in T-ALL cell lines. Neither was there significant correlation with BIM, PUMA or BCL-2 that have been shown to be key initiators of both GC and g-irradiation-induced apoptosis (Erlacher et al, 2005).…”

Section: Canonical Gc-resistance Mechanisms In T-all Cell Linescontrasting

confidence: 99%

Glucocorticoid resistance in T-lineage acute lymphoblastic leukaemia is associated with a proliferative metabolism

et al. 2009

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Glucocorticoids (GCs) are among the most important drugs for acute lymphoblastic leukaemia (ALL), yet despite their clinical importance, the exact mechanisms involved in GC cytotoxicity and the development of resistance remain uncertain. We examined the baseline profile of a panel of T-ALL cell lines to determine factors that contribute to GC resistance without prior drug selection. Transcriptional profiling indicated GC resistance in T-ALL is associated with a proliferative phenotype involving upregulation of glycolysis, oxidative phosphorylation, cholesterol biosynthesis and glutamate metabolism, increased growth rates and activation of PI3K/AKT/mTOR and MYC signalling pathways. Importantly, the presence of these transcriptional signatures in primary ALL specimens significantly predicted patient outcome. We conclude that in lymphocytes the activation of bioenergetic pathways required for proliferation may suppress the apoptotic potential and offset the metabolic crisis initiated by GC signalling. It is likely that the link between GC resistance and proliferation in T-ALL has not been fully appreciated to date because such effects would be masked in the context of current multiagent therapies. The data also provide the first evidence that altered expression of wild-type MLL may contribute to GC-resistant phenotypes. Our findings warrant the continued development of selective metabolic inhibitors for the treatment of ALL.

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Section: Canonical Gc-resistance Mechanisms In T-all Cell Linescontrasting

confidence: 99%

Glucocorticoid resistance in T-lineage acute lymphoblastic leukaemia is associated with a proliferative metabolism

et al. 2009

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“…Using patterns of gene expression, the authors were able to distinguish a subgroup of ALL tumors with cross-chemoresistance and unfavorable outcome from those which exhibited only single-drug resistance. The same study also showed that transcriptional regulation of key apoptosis genes can be linked to cellular drug resistance and prognosis in pediatric B-lineage ALL (29). The present case may reflect the same manner of drug-resistance due to the large number of chromosome breaks and aberrations involved.…”

Section: Discussionsupporting

confidence: 68%

A unique complex translocation involving six different chromosomes in a case of childhood acute lymphoblastic leukemia with the Philadelphia chromosome and adverse prognosis

Achkar

Wafa²,

Mkrtchyan³

et al. 2010

Oncology Letters

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Abstract. Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Approximately 84% of cases of ALL are classified as B-precursor ALL, 14% of cases are T-cell and 2% of cases are B-cell (B-)ALL. About one third of B-ALL cases show an abnormal karyotype. Combining data obtained by immunophenotyping, karyotyping and molecular cytogenetic analyses allows for a better understanding of this heterogeneous disease. This study reports an exceptional B-ALL case with a poor prognosis and unique complex chromosomal aberrations not previously observed, i.e., a translocation involving the six chromosomal regions 1q42, 4q21, 4q24, 4q35 (twice), 8q22 and 10p15.3 besides 9q34 and 22q11.2.

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“…Survivin may, however, not only function as a risk factor discriminating patients with poor prognosis but also serve as a therapeutic target with the aim of specifically eliminating those cells that drive the disease and trigger relapse [26]. In addition to therapeutic blockage of survivin activity by antisense oligonucleotides or pharmacological inhibitors [27,28].…”

Section: Discussionmentioning

confidence: 99%

Prognostic Significance of Survivin in Pediatric Acute Lymphoblastic Leukemia

Esh

Atfy

Azizi

et al. 2011

Indian J Hematol Blood Transfus

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Impaired apoptosis is mediated by members of the inhibitor of apoptosis proteins (IAP) family such as survivin. Survivin was described in number of different tumors and found to correlate with poor prognosis in a variety of cancers including hematologic malignancies. The aim of this study was to determine survivin in pediatric ALL and compare it with clinical and hematological findings, response to therapy and outcome. Flowcytometry was used for detection of intracellular survivin and determine its mean fluorescence intensity (MFI) in bone marrow mononuclear cells. Patients were followed up for 28 months after induction therapy. Survivin was detected in 63.3% of the patients BM. In spite of no association of survivin levels with established risk factors (P [ 0.05) except with high WBC, there was significant higher level of survivin expression in high risk group patients when patients were stratified into high and standard risk groups. According to response to induction therapy, there was no significant difference, in survivin level between patients who achieved CR, RD and ED. However, patients suffering relapse of the disease, had a significant higher basal level of survivin than patients still in remission. Over expression of survivin is a candidate parameter to determine poor prognosis in ALL patients and it may serve to refine treatment stratification with intensification of therapy in those patients prone to relapse.

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The expression of 70 apoptosis genes in relation to lineage, genetic subtype, cellular drug resistance, and outcome in childhood acute lymphoblastic leukemia

Cited by 127 publications

References 68 publications

Glucocorticoid resistance in T-lineage acute lymphoblastic leukaemia is associated with a proliferative metabolism

Glucocorticoid resistance in T-lineage acute lymphoblastic leukaemia is associated with a proliferative metabolism

A unique complex translocation involving six different chromosomes in a case of childhood acute lymphoblastic leukemia with the Philadelphia chromosome and adverse prognosis

Prognostic Significance of Survivin in Pediatric Acute Lymphoblastic Leukemia

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