MicroRNAs (miRNAs) are involved in the management of hematopoiesis. As a consequence, miRNA dysregulation causes disruption of the hematopoietic system and leukemia may arise. We here comprehensively ...discuss miRNAs found discriminative for cytogenetic and molecular subtypes of acute leukemia. These miRNAs are either known miRNAs involved in leukemogenesis with proven tumor suppressor or oncogenic activities or are newly identified by high-throughput sequencing with yet unknown function. Furthermore, forces are outlined that drive aberrant miRNA function, which include genetic abnormalities (for example, deletions, translocations and mutations) and epigenetic aberrations (for example, aberrant DNA methylation or histone modifications). Interestingly, leukemia-silenced miRNAs can be re-expressed upon treatment with de-methylating agents. Targeting miRNA expression may serve a therapeutical role, albeit at present this way of targeted therapy is in its infancy. However, emerging knowledge about the biology of miRNAs in leukemia may result into a role for these miRNAs in the diagnosis and treatment of acute leukemia.
MicroRNA regulate the activity of protein-coding genes including those involved in hematopoietic cancers. The aim of the current study was to explore which microRNA are unique for seven different ...subtypes of pediatric acute lymphoblastic leukemia.
Expression levels of 397 microRNA (including novel microRNA) were measured by quantitative real-time polymerase chain reaction in 81 cases of pediatric leukemia and 17 normal hematopoietic control cases.
All major subtypes of acute lymphoblastic leukemia, i.e. T-cell, MLL-rearranged, TEL-AML1-positive, E2A-PBX1-positive and hyperdiploid acute lymphoblastic leukemia, with the exception of BCR-ABL-positive and 'B-other' acute lymphoblastic leukemias (defined as precursor B-cell acute lymphoblastic leukemia not carrying the foregoing cytogenetic aberrations), were found to have unique microRNA-signatures that differed from each other and from those of healthy hematopoietic cells. Strikingly, the microRNA signature of TEL-AML1-positive and hyperdiploid cases partly overlapped, which may suggest a common underlying biology. Moreover, aberrant down-regulation of let-7b (~70-fold) in MLL-rearranged acute lymphoblastic leukemia was linked to up-regulation of oncoprotein c-Myc (P(FDR)<0.0001). Resistance to vincristine and daunorubicin was characterized by an approximately 20-fold up-regulation of miR-125b, miR-99a and miR-100 (P(FDR)≤0.002). No discriminative microRNA were found for prednisolone response and only one microRNA was linked to resistance to L-asparaginase. A combined expression profile based on 14 microRNA that were individually associated with prognosis, was highly predictive of clinical outcome in pediatric acute lymphoblastic leukemia (5-year disease-free survival of 89.4%±7% versus 60.8±12%, P=0.001).
Genetic subtypes and drug-resistant leukemic cells display characteristic microRNA signatures in pediatric acute lymphoblastic leukemia. Functional studies of discriminative and prognostically important microRNA may provide new insights into the biology of pediatric acute lymphoblastic leukemia.
MicroRNAs (miRNAs) control the expression of protein-coding genes in normal hematopoietic cells and, consequently, aberrant expression may contribute to leukemogenesis. To identify miRNAs relevant to ...pediatric acute lymphoblastic leukemia (ALL), we cloned 105 known and 8 new miRNA genes expressed in patients' leukemia cells. Instead of known miRNA genes, new miRNA genes were not evolutionarily conserved. Quantification of 19 selected miRNA genes revealed an aberrant expression in ALL as compared with normal CD34+ cells (P <or= 0.02); both upregulated (14/19) and downregulated (5/19) expressions were observed. Eight miRNAs were differentially expressed between MLL and non-MLL precursor B-ALL cases (P<0.05). Most remarkably, miR-708 was 250- up to 6500-fold higher expressed in 57 TEL-AML1, BCR-ABL, E2A-PBX1, hyperdiploid and B-other cases than in 20 MLL-rearranged and 15 T-ALL cases (0.0001<P<0.01), whereas the expression of miR-196b was 500-fold higher in MLL-rearranged and 800-fold higher in 5 of 15 T-ALL cases as compared with the expression level in the remaining precursor B-ALL cases (P<0.001). The expression did not correlate with the maturation status of leukemia cells based on immunoglobulin and T-cell receptor rearrangements, immunophenotype or MLL-fusion partner. In conclusion, we identified new miRNA genes and showed that miRNA expression profiles are ALL subtype-specific rather than linked to the differentiation stadium associated with these subtypes.
Quality of life (QoL) is impaired in many cancer patients. The aim of this study was to test whether detriments in QoL were less pronounced in global assessments of QoL compared to more specific ...components. A total of 2059 cancer patients with mixed diagnoses were examined 6 months after discharge from a cancer rehabilitation clinic. QoL was measured with the EORTC QLQ‐C30, which contains a global QoL scale, and 14 functioning and symptom scales and symptom items. A sample of the general population (n = 4476) served as controls. Regression analyses were performed to calculate expected mean scores for the patients, based on their age and gender distribution. Global QoL in the cancer sample (M = 69.3) was nearly equal to that of the general population, while the mean scores of all functioning scales, symptom scales and symptom items showed markedly worse QoL. This general relationship between global and specific QoL was found for seven of eight cancer types. The results indicate that global QoL is not the sum of its parts. This should be considered when treatment effects on QoL are examined. One alternative is to use higher order summarising functioning and symptom scales.
MLL-rearranged acute lymphoblastic leukemia (ALL) in infants (<1 year) is the most aggressive type of childhood leukemia. To develop more suitable treatment strategies, a firm understanding of the ...biology underlying this disease is of utmost importance. MLL-rearranged ALL displays a unique gene expression profile, partly explained by erroneous histone modifications. We recently showed that t(4;11)-positive infant ALL is also characterized by pronounced promoter CpG hypermethylation. In this study, we investigated whether this widespread hypermethylation also affected microRNA (miRNA) expression. We identified 11 miRNAs that were downregulated in t(4;11)-positive infant ALL as a consequence of CpG hypermethylation. Seven of these miRNAs were re-activated after exposure to the de-methylating agent Zebularine. Interestingly, five of these miRNAs are associated either with MLL or MLL fusions, and for miR-152 we found both MLL and DNA methyltransferase 1 (DNMT1) as potential targeted genes. Finally, a high degree of methylation of the miR-152 CpG island was strongly correlated with a poor clinical outcome. Our data suggests that inhibitors of methylation have a potential beyond re-expression of hypermethylated protein-coding genes in t(4;11)-positive infant ALL. In this study, we provide additional evidence that they should be tested for their efficacy in MLL-rearranged infant ALL in in vivo models.
MicroRNAs (miRNAs) relevant to acute lymphoblastic leukemia (ALL) in children are hypothesized to be largely unknown as most miRNAs have been identified in non-leukemic tissues. In order to discover ...these miRNAs, we applied high-throughput sequencing to pooled fractions of leukemic cells obtained from 89 pediatric cases covering seven well-defined genetic types of ALL and normal hematopoietic cells. This resulted into 78 million small RNA reads representing 554 known, 28 novel and 431 candidate novel miR genes. In all, 153 known, 16 novel and 170 candidate novel mature miRNAs and miRNA-star strands were only expressed in ALL, whereas 140 known, 2 novel and 82 candidate novel mature miRNAs and miRNA-star strands were unique to normal hematopoietic cells. Stem-loop reverse transcriptase (RT)-quantitative PCR analyses confirmed the differential expression of selected mature miRNAs in ALL types and normal cells. Expression of 14 new miRNAs inversely correlated with expression of predicted target genes (-0.49 ≤ Spearman's correlation coefficients (Rs)≤ -0.27, P ≤ 0.05); among others, low levels of novel sol-miR-23 associated with high levels of its predicted (antiapoptotic) target BCL2 (B-cell lymphoma 2) in precursor B-ALL (Rs -0.36, P = 0.007). The identification of >1000 miR genes expressed in different types of ALL forms a comprehensive repository for further functional studies that address the role of miRNAs in the biology of ALL.
There has been a considerable debate over the merits of a pre- or intraoperative drainage of giant ovarian cysts, which represented a very frequent approach before definitive surgery in the past. ...Including our presented case of a 57-year-old woman with a 49 kg mucinous cystadenoma, 19 patients with giant ovarian cysts weighing more than 40 kg were reported in the literature since 1970. An incidence of 37% of malignant and low malignant potential tumors was found. Based on a critical evaluation of the medical courses and the discussed miscellaneous advantages and complications, we conclude that a pre- and intraoperative drainage should be avoided.
PDF
