A gene expression profile associated with relapse of cytogenetically normal acute myeloid leukemia is enriched for leukemia stem cell genes

Some 50 – 80% of patients with acute myeloid leukemia (AML) achieve a complete remission with contemporary chemotherapy protocols, yet the majority of them eventually relapse with resistant disease: some patients no longer respond to chemotherapy at disease recurrence; others accomplish second and even third remissions whose decreasing duration nevertheless indicates that the pool of residual leukemic cells, i.e. of cells that persisted during treatment with cytotoxic drugs, increases with every round of therapy [1]. Either of these clinical courses therefore refl ects an enhanced chemotherapy resistance of leukemic cells at relapse as compared to the cell population at diagnosis. Molecular changes enabling malignant cells to survive exposure to cytotoxic drugs may already have been present in a subset of the leukemic cell population at presentation, or may emerge during treatment [2,3], but in any case are thought to be selected as a consequence of drug therapy, and to play a major role in therapy resistance at relapse. Remarkably, however, even though various types of molecular alterations may be acquired at relapse, neither specifi c cytogenetic alterations nor functionally relevant point mutations as identifi ed by whole genome sequencing were associated with relapse in a recurrent manner [2,3]. Certain copy number variations and known AML associated point mutations were newly present at relapse in small proportions of patients (usually 10%), but the latter were lost in other patients, indicating that they are unlikely to represent drivers of therapy resistance at disease recurrence [4]. Th ese fi ndings could either indicate that chemotherapy resistance at relapse is acquired through a large variety of different mechanisms, or that molecular changes of other types than those mentioned above are of more general relevance in this context. Indeed, an earlier study has suggested that the expression of specifi c genes may change in a consistent manner between diagnosis and relapse of AML [5]. However, only a limited number of genes and mostly unpaired samples were probed in this investigation. Th erefore, in the present study, genes whose expression changed in a relapse-specifi c manner were sought in a set of paired AML samples and on a genome-wide scale. To limit the genetic heterogeneity of the study population, only samples from patients with cytogenetically normal (CN) AML were used.Letter to the Edito

A gene expression profile associated with relapse of cytogenetically normal acute myeloid leukemia is enriched for leukemia stem cell genes

Some 50 – 80% of patients with acute myeloid leukemia (AML) achieve a complete remission with contemporary chemotherapy protocols, yet the majority of them eventually relapse with resistant disease: some patients no longer respond to chemotherapy at disease recurrence; others accomplish second and even third remissions whose decreasing duration nevertheless indicates that the pool of residual leukemic cells, i.e. of cells that persisted during treatment with cytotoxic drugs, increases with every round of therapy [1]. Either of these clinical courses therefore refl ects an enhanced chemotherapy resistance of leukemic cells at relapse as compared to the cell population at diagnosis. Molecular changes enabling malignant cells to survive exposure to cytotoxic drugs may already have been present in a subset of the leukemic cell population at presentation, or may emerge during treatment [2,3], but in any case are thought to be selected as a consequence of drug therapy, and to play a major role in therapy resistance at relapse. Remarkably, however, even though various types of molecular alterations may be acquired at relapse, neither specifi c cytogenetic alterations nor functionally relevant point mutations as identifi ed by whole genome sequencing were associated with relapse in a recurrent manner [2,3]. Certain copy number variations and known AML associated point mutations were newly present at relapse in small proportions of patients (usually 10%), but the latter were lost in other patients, indicating that they are unlikely to represent drivers of therapy resistance at disease recurrence [4]. Th ese fi ndings could either indicate that chemotherapy resistance at relapse is acquired through a large variety of different mechanisms, or that molecular changes of other types than those mentioned above are of more general relevance in this context. Indeed, an earlier study has suggested that the expression of specifi c genes may change in a consistent manner between diagnosis and relapse of AML [5]. However, only a limited number of genes and mostly unpaired samples were probed in this investigation. Th erefore, in the present study, genes whose expression changed in a relapse-specifi c manner were sought in a set of paired AML samples and on a genome-wide scale. To limit the genetic heterogeneity of the study population, only samples from patients with cytogenetically normal (CN) AML were used.Letter to the Edito

Ex-post Evaluierung der Kompetenzzentrenprogramme Kplus und K_ind/K_net

Die Evaluierung wurde im Auftrag des Bundesministeriums für Verkehr, Innovation und Technologie (BMVIT) sowie des Bundesministeriums für Wirtschaft, Familie und Jugend (BMWFJ) durchgeführt. Das Ziel der Evaluierung war es, unter Einsatz eines geeigneten Methodenportfolios die Einbettung der Kompetenzzentrenprogramme in das österreichische Innovationssystem sowie Effekte und Wirkungen zu bewerten. Die K‐Programme bildeten die ersten bedeutenden, mit erheblichen finanziellen Mitteln ausgestatteten Programme zur strukturellen Förderung von Wissenschaft‐Wirtschaft‐Kooperationen in Österreich. Die Ausdifferenzierung der K‐Programme in unterschiedliche Förderschienen (wissenschaftsgetrieben (Kplus), anwendungsgetrieben und gebündelt (K_ind), anwendungsgetrieben und verteilt (K_net)) hatte eine konzeptionelle Berechtigung und war für die Anfangsphase der Programmentwicklung hilfreich. Trotzdem ist die Initiierung von zwei Programmen aus heutiger Sicht auch eine zweifelhafte organisatorische Parallelentwicklung, und nicht zuletzt den überlappenden Kompetenzen der Ministerien im Bereich FTI‐Politik geschuldet. Die ex‐post Evaluierung der Kompetenzzentrenprogramme nimmt eine abschließende Bewertung eines der größten österreichischen Strukturprogramme vor und liefert Hinweise für die Gestaltung rezenter und zukünftiger Fördermaßnahmen

Frequent Down Regulation of the Tumor Suppressor Gene A20 in Multiple Myeloma

<div><p>Multiple myeloma (MM) is a malignant clonal expansion of plasma cells in the bone marrow and belongs to the mature B-cell neoplams. The pathogenesis of MM is associated with constitutive NF-κB activation. However, genetic alterations causing constitutive NF-κB activation are still incompletely understood. Since A20 (<i>TNFAIP3</i>) is a suppressor of the NF-κB pathway and is frequently inactivated in various lymphoid malignancies, we investigated the genetic and epigenetic properties of A20 in MM. In total, of 46 patient specimens analyzed, 3 single base pair exchanges, 2 synonymous mutations and one missense mutation were detected by direct sequencing. Gene copy number analysis revealed a reduced A20 gene copy number in 8 of 45 (17.7%) patients. Furthermore, immunohistochemical staining confirmed that A20 expression correlates with the reduction of A20 gene copy number. These data suggest that A20 contributes to tumor formation in a significant fraction of myeloma patients.</p></div

Genetic aberrations of A20 in multiple myeloma.

<p><b>a: Electropherogram of rs368271377 in exon 7:</b> Arrows indicate the single base pair substitution. <b>b: Electropherogram of rs143002189 in exon 9:</b> The arrow indicates the single base pair substitution. <b>c: Gene copy number analysis of A20 of selected cases:</b> For the gene copy number assays two technical replicates of each samples were used. The blue bar represents the data for exon 4 and the red one for exon 6. Each bar represents the mean values of expression levels ± standard deviation (SD). Cut off for deletion—depicted as red line—was set at 0.7 through the fact that samples exhibited up to 40% non-neoplastic surrounding tissue. <b>d: Representative immunohistochemical A20 staining of multiple myeloma samples.</b> i and ii: multiple myeloma samples with reduced A20 gene copy number. iii and iv: multiple myeloma samples with normal A20 gene copy number.</p

mRNA expression analysis of A20 and 7 NF-κB target genes (BCL2, Cyclin D1, CCR7, CD44, CXCR2, cFlip, IRF4) of MM cases with (n = 6) and without (n = 14) monoallelic A20 deletions and of non-neoplastic bone marrow biopsies (BM; n = 6).

<p>mRNA expression levels were calculated as relative expression in comparison with peripheral mononucleated cells serving as a calibrator. Each bar represents the mean values of expression levels ± standard deviation (SD). The comparison of the expression levels was performed by using the Mann-Whitney U test; all significant associations were corrected for multiple testing by applying a Bonferroni correction.</p