CASP8AP2 is a promising prognostic indicator in pediatric acute lymphoblastic leukemia

The prognostic significance of caspase 8 associated protein 2 (CASP8AP2) in pediatric ALL is controversial. We determined a cut-off of CASP8AP2 expression in bone marrow samples of 39 newly diagnosed patients, and found a significantly poor bone marrow relapse-free survival (p = 0.019) in low-expression group and verified it in another cohort of 106 patients (p = 0.002). Furthermore, as an independent prognostic factor, CASP8AP2 expression was correlated to minimal residual disease (MRD), and incorporating it with MRD would help to identify patients at greater risk of bone marrow relapse. We also developed an algorithm comprised of clinical risk and CASP8AP2 expression, which could predict bone marrow relapse more accurately.     

SMYD2 is highly expressed in pediatric acute lymphoblastic leukemia and constitutes a bad prognostic factor

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy. Although several clinical characteristics can be associated with worse prognosis, more robust biological markers still remains uncovered. SMYD2, a member of SMYD protein family, regulates the activity of several proteins through methylation. In this study, we performed quantitative real time PCR to compare the expression of SMYD2 in 83 pediatric ALL patients and non-neoplastic bone marrow samples (BMS). The study revealed that SMYD2 expression is altered in ALL BMS and its high expression was correlated with a bad prognosis. Moreover, we also revealed that SMYD2 expression level significantly decreases in patients that respond to chemotherapy treatment.     

儿童急性淋巴细胞白血病在德国的治疗--COALL-92方案521例临床及疗效分析

目的：总结分析德国应用ＣＯＡＬＬ－９２方案（Ｃooperative mrlticenter treatment strdy for childhood with acute lymphoblastic leukemia of the German Pediatric Oncology and Hematology Society ＣＯＡＬＬ－９２－Ｓtudy/ＧＰＯＨ）治疗儿童急性淋巴细胞白血病的临床疗效。方法：１９９２～１９９７年间在德国１９所儿童 肿瘤治疗中心人同合作采用统一的诊断标准及治疗方案（ＣＯＡＬＬ－９２－ＳＴＵＤＹ/ＧＰＯＨ）治     

Significance of CD66c expression in childhood acute lymphoblastic leukemia

Upon analyzing 696 childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cases, we identified the characteristics of CD66c expression. In addition to the confirmation of strong correlation with BCR-ABL positivity and hyperdiploid, we further observed that CD66c is frequently expressed in CRLF2-positive (11/15, p < 0.01 against chimeric gene-negative) as well as hypodiploid cases (3/4), whereas it is never expressed in ETV6-RUNX1, MLL-AF4, MLL-AF9, MLL-ENL, and E2A-PBX1-positive cases. Although the expression of CD66c itself is not directly linked to the prognosis, the accompanying genetic abnormalities are important prognostic factors for BCP-ALL, indicating the importance of CD66c expression in the initial diagnosis of BCP-ALL.     

l-Asparagine depletion levels and l-asparaginase activity in plasma of children with acute lymphoblastic leukemia under asparaginase treatment

Purpose To determine the minimum levels of l-asparaginase (ASNase) activity necessary to maintain l-asparagine (Asn) depletion under ASNase treatment in acute lymphoblastic leukemia (ALL).Methods We measured ASNase activity using an enzyme coupling method with a limit of detection of 2 U/l and examined the relationship between ASNase activity and Asn levels in blood samples from 14 children with ALL.Results In all but one patient showing high ASNase antibody titers, minimum ASNase activity to maintain Asn depletion levels below the limit of detection (40 ng/ml) ranged from 6 to 180 U/l with a median value of 16 U/l. In 11 patients, the enzyme activity corresponding to minimum detectable Asn levels ranged from 2 to 32 U/l with a median value of 6.5 U/l. Patients with an ASNase activity of 2 U/l or an undetectable activity (<2 U/l) had nearly normal Asn levels: 4140±1161 ng/ml at 2 U/l and 7235±3107 ng/ml at <2 U/l (mean±SD). Statistical analysis showed that ASNase activity in the range of 2–32 U/l was inversely correlated with Asn levels (r=–0.803, P=0.001).Conclusion These results show that Asn levels are strongly correlated with plasma ASNase activity even at low enzyme activities (<50 U/l) and that this sensitive ASNase assay can be used to estimate plasma Asn depletion levels.Abbreviations ALL Acute lymphoblastic leukemia - Asn Asparagine - ASNase Asparaginase - SSA Sulfosalicylic acid     

miR-141在儿童急性B淋巴细胞白血病中的表达及意义

背景与目的：微小RNA(microRNA,miRNA)是一类长度为21~25 nt的内源性单链非编码RNA小分子。本研究旨在探讨miR-141在儿童急性B淋巴细胞白血病(acute lymphoblastic leukemia,ALL)中的表达及临床意义。方法：收集B细胞ALL患儿35例为B细胞ALL组,以非血液病患儿15例为对照组,采集骨髓标本,提取总RNA,采用real-time PCR检测miR-141的表达,比较各组miR-141表达差异。结果：miR-141在B细胞ALL组中的表达低于对照组(P<0.05);miR-141在治疗前的表达明显低于治疗第30天及第12周(P<0.05),治疗第30天的表达低于治疗第12周(P<0.05);≥10岁组miR-141的表达低于＜10岁组(P<0.05);低危组治疗前miR-141表达高于中、高危组(P<0.05),而中危组高于高危组(P<0.05)。结论：miR-141在儿童B细胞ALL中很可能存在抑癌作用,并是预后预测的潜在靶点。     

Predictors of outcome in adults with BCR-ABL negative acute lymphoblastic leukemia treated with a pediatric-based regimen

We retrospectively evaluated the outcome of 156 adults age 17–60 with BCR-ABL negative acute lymphoblastic leukemia treated with a pediatric-inspired protocol. The CR rate was 93%; 5-year overall survival (OS) and disease-free survival were 66% and 70%, respectively. Age <34 years and low presenting WBC were independent predictors of favorable OS (p < 0.0001). The 5 year OS of patients age <34 and 34–60 presenting with a low WBC were 85% and 57%, respectively; the 5 year OS for those presenting with a high WBC were 57% and 30%, respectively. Cytogenetics and phenotype were not independent predictors of OS.     

急性淋巴细胞白血病患者DNA拓扑异构酶的表达及临床意义

 目的 探讨急性淋巴细胞白血病（ALL）患者DNA拓扑异构酶（Topo）mRNA水平的表达及其临床意义。方法 用半定量反转录-聚合酶链反应（RT-PCR）技术检测了90例ALL患者DNA Topo的表达。结果 DNA Topo各亚型（Topo-Ⅰ,Topo-Ⅱa,Topo-Ⅱb）的表达阳性率初治组（58.1 %,51.2 %,81.5 %）高于复发难治组（33.3 %,44.4 %,77.9 %）和完全缓解（CR）组（14.9 %,23.4 %,34.1 %）,各组比较差异均有统计学意义（P＜0.05）。表达量各组间比较,CR组与初治组差异有统计学意义（P＜0.005）;CR组与复发难治组Topo-Ⅱb差异有统计学意义（P＜0.05）,DNA To各亚型表达量之间有显著相关性（P＜0.001）,且各亚型表达量与WBC数之间亦有显著相关性（P＜0.01）。结论 ALL患者DNA Topo各亚型mRNA水平的表达量可能与WBC数共同作为Topo抑制剂药物个体化合理用药的参考指标,但不宜作为判断患者是否对Topo抑制剂耐药的参考指标。     

Apoptosis pathway signature for prediction of treatment response and clinical outcome in childhood high risk B-Precursor acute lymphoblastic leukemia

The most common cancer in children is acute lymphoblastic leukemia (ALL) and it had high cure rate, especially for B-precursor ALL. However, relapse due to drug resistance and overdose treatment reach the limitations in patient managements. In this study, integration of gene expression microarray data, logistic regression, analysis of microarray (SAM) method, and gene set analysis were performed to discover treatment response associated pathway-based signatures in the original cohort. Results showed that 3772 probes were significantly associated with treatment response. After pathway analysis, only apoptosis pathway had significant association with treatment response. Apoptosis pathway signature (APS) derived from 15 significantly expressed genes had 88% accuracy for treatment response prediction. The APS was further validated in two independent cohorts. Results also showed that APS was significantly associated with induction failure time (adjusted hazard ratio [HR] = 1.60, 95% confidence interval [CI] = [1.13, 2.27]) in the first cohort and significantly associated with event-free survival (adjusted HR = 1.56, 95% CI = [1.13, 2.16]) or overall survival in the second cohort (adjusted HR = 1.74, 95% CI = [1.24, 2.45]). APS not only can predict clinical outcome, but also provide molecular guidance of patient management.     

Immunophenotyping of childhood acute lymphoblastic leukemia in Saudi Arabia: Second look

Geographical variations in the incidence of disease are of considerable theoretical and practical importance. It has been claimed that the distribution of acute lymphoblastic leukemia (ALL) phenotypes in Saudi Arabia is different from that recorded in the Western literature. One hundred and twelve (112) patients under 15 years of age, diagnosed as ALL between January 1992 and May 1994 had immunophenotypes performed on their blast cells. Common ALL (cALL) together with pre-B-ALL, formed 86.5% of the total; B-cell 3%, T-cell 6% and null cell 4.5%. These figures are not significantly different from the Western literature. A previous claim from this institution in 1990, that both null and B-cell ALL were significantly increased compared with elsewhere, is not supported by the present figures. Age and sex distribution, and FAB classification, L1 77%, L2 20% and L3 3%, were also of the same order as described elsewhere and, in particular, there was no increase in the frequency of L3 subtype.     

Prophylaxis and treatment of neoplastic meningeosis in childhood acute lymphoblastic leukemia

The introduction of cranial radiotherapy (CRT) has provided efficient control of overt or subclinical meningeosis in acute leukemia. Especially due to the long-term toxicity of CRT, reduction or elimination of radiotherapy appeared mandatory after cure rates of more than 70% had been achieved in acute lymphoblastic leukemia (ALL). Several large clinical trials of the Berlin-Frankfurt-Münster (BFM) Study Group with more than 3500 patients since 1981 have demonstrated that intensive systemic and intrathecal chemotherapy without or with limited CRT can efficiently prevent central nervous system (CNS) relapses in a large percentage of patients. However, only in low-risk patients prophylactic radiotherapy can be completely and safely replaced by conventional doses of methotrexate. In addition, reduction of chemotherapy in low-risk ALL increased the rate of relapses with CNS involvement. Thus, only a combination of multidrug induction, high-dose methotrexate (HD-MTX) consolidation, and reintensification allowed safe elimination of CRT in low-risk ALL. This approach combined with CRT with 12Gy and 18 Gy in medium and high risk ALL, respectively, reduced the incidence of relapses with CNS involvement to less than 5% (trial ALL-BFM 86). Patients with inadequate response to therapy, or with T-cell ALL, or with overt CNS disease are at particularly high risk for relapse with CNS involvement, and require more systemic and intrathecal chemotherapy combined with cranial irradiation. In B-cell ALL, short intensive chemotherapy pulses including HD-MTX could completely replace radiotherapy. In AML, post-consolidation CRT appears to be advantageous with regard to control of extramedullary as well as systemic relapses.     

儿童急性淋巴细胞白血病中p15基因缺失及转录异常的研究

目的：探讨ｐ１５基因缺失及表达异常在儿童急性淋巴细胞白血病（ＡＬＬ）发病中的作用。方法;采用Ｓｏｕｔｈｅｒｎ ｂｌｏｔ方法检测了５３例儿童ＡＬＬ骨髓样品中ｐ１５基因的缺失;用逆转录－聚合酶链反应（ＲＴ－ＰＣＲ０检测了２９例样品中ｐ１５ ｍＲＮＡ的转录。结果：全部被检样品中ｐ１５基因缺失１１例,缺失率为２０．８％,其中,９例Ｔ细胞型ＡＬＬ（Ｔ－ＡＬＬ）中５例显示有ｐ１５基因缺失,缺失率５５．６％;而     

DDX43 promoter is frequently hypomethylated and may predict a favorable outcome in acute myeloid leukemia

DEAD box polypeptide 43 (DDX43), a cancer/testis antigen (CTA), has been found to be overexpressed in various solid tumors and some hematologic malignancies. In the present work hypomethylation of the DDX43 gene was detected in 15% (32/214) of primary acute myeloid leukemia (AML) using real-time quantitative methylation-specific PCR (RQ-MSP). The level of DDX43 expression was correlated with DDX43 hypomethylation (R = 0.277, P = 0.014). Moreover, bisulfite sequencing confirmed the significant correlation between the methylation density and the level of DDX43 hypomethylation. Additionally, restoration of DDX43 expression in the K562 cell line by 5-aza-2′-deoxycytidine treatment confirmed a direct contribution of methylation in regulating the DDX43 gene. DDX43 hypomethylation was observed more frequently in favorable group (21.4%) and intermediate group (15.8%) than in poor group (0%) (P = 0.009). AML patients with DDX43 hypomethylation had a better overall survival (median not obtained) than those with DDX43 methylation (median 8 months, 95% confidence interval 5.6–10.4 months) (P = 0.014). In summary, the DDX43 gene is activated by promoter hypomethylation and DDX43 hypomethylation may be a favorable prognostic factor in AML.     

Cytogenetics and their prognostic value in childhood and adult acute lymphoblastic leukemia (ALL) excluding L3

Cytogenetic analysis was made at diagnosis in 174 cases of ALL (101 children less than 20 years and 73 adults), excluding Burkitt's ALL (L3). In 11 children (11 per cent) insufficient material was obtained. In the remaining 90, 50 (56 per cent) had a normal karyotype, 20 (22 per cent) a hyperdiploid karyotype, five (6 per cent) a hypodiploid karyotype, 12 (13 per cent) had a translocation (including seven cases of t(1;19)) and three had a pseudodiploid karyotype without translocation. Ninety-eight per cent of patients reached complete remission (CR). Median actuarial CR duration was not attained, was 50 months, 13 months and 11 months respectively in patients with hyperdiploid, normal, hypodiploid karyotype and in patients with a translocation, the difference between subgroups being significant. In a Cox model, cytogenetics were the strongest factor predicting CR duration (p = 0.03) followed by leukocytes (p = 0.04), whereas the presence of ‘bulky disease’ had a borderline value (p = 0.077). Of note was that 9/17 (53 per cent) patients with a hypodiploid karyotype or a translocation had no ‘risk factors’ before cytogenetic analysis. In adults, cytogenetic analysis was unsuccessful in 15 (20 per cent) of patients. In the remaining 58 cases, 19 (33 per cent) had a normal karyotype, 15 (26 per cent) had a hyperdiploid, one (2 per cent) had a hypodiploid karyotype, 19 (33 per cent) had a translocation (including 12 t(9;22)), and four (7 per cent) had a pseudodiploid without translocation. 73 per cent patients reached CR. Median actuarial DFS was 12.5 months. No significant differences in CR rate and CR duration were seen between cytogenetic groups, but median CR duration was slightly longer in patients with a normal karyotype (17 months) and shorter in patients with t(9; 22) (8.5 months). Only 3/12 of the latter had major risk factors before cytogenetic analysis. Cytogenetic analysis is important in ALL, especially in patients with otherwise standard risk factors, as it may reveal unexpected translocations or hypodiploidy, which may require a therapeutic reinforcement.     

Prognostic significance of karyotype analysis in children with acute lymphoblastic leukemia.

Chromosome studies, using bone marrow samples of 26 pretreated children (below 15 years of age) with Acute Lymphoblastic Leukemia were carried out to explore the potentialities of applying chromosomal findings as a prognostic indicator in these patients. Abnormal karyotype was identified in 15 patients (57.6 per cent). The chromosomes frequently involved in non-random numerical abnormalities were Nos. 8, 18 and 21. Structural chromosome changes observed consisted of deletion 6q- and translocation t (4;11). After karyotype analysis, patients were grouped into subsets on the basis of the karyotype pattern observed. They were followed up to evaluate their prognosis and survival period. Patients showing hyperdiploid clone with greater than 51 chromosomes had the best prognosis. Patients with normal karyotype and patients with deletion of the long arm of chromosome 6 showed intermediate prognosis whereas patients showing t (4;11), trisomy 8, trisomy 18, trisomy 21, and hypodiploid karyotype were associated with worst prognosis. Thus, karyotype analysis before treatment helps to classify ALL patients as poor, intermediate and good prognosis groups and on this basis therapy can be designed accordingly.     

Mutations of perforin gene in Chinese patients with acute lymphoblastic leukemia

To address whether mutations and single nucleotide polymorphisms (SNPs) in perforin gene (PRF1) are correlated with acute lymphoblastic leukemia (ALL) in Chinese, we screened mutations in codon region of PRF1 in 111 ALL patients, and correlated the results with patients’ immunophenotype, karyotype and fusion genes. Four novel monoallelic missense and two novel monoallelic synonymous mutations (G198R, R225Q, D486G, R509K, S388S and Q540Q) were identified in 9 B-ALL, of whom 7 cases carried BCR-ABL gene, one carried MLL-AF4 fusion gene, and one lost two chromosomes. Our results suggest that mutations in PRF1 may play a role in the pathogenesis of B-ALL.     

费城染色体样急性淋巴细胞白血病基因改变及治疗研究进展

费城染色体样急性淋巴细胞白血病(Ph-like ALL)涉及与其高危特点和预后不良相关的多种基因组改变,如IKZF1 、CRLF2、JAK1/2、EBF1-PDGFRB、ATF7IP、EPOR、SH2B3等.JAK/STAT途径和PI3K/mTOR途径已被证实很可能是某些Ph-like ALL的相关靶点,文章重点综述以上基因组改变及治疗进展.