Ikaros 与儿童急性淋巴细胞白血病

Ikaros 是造血细胞分化和免疫系统发育的重要调节因子,并且作为肿瘤抑制因子,Ikaros异常会阻滞 T、B 细胞的发育或导致肿瘤形成。在白血病患者中,Ikaros 发生突变导致患者治疗反应下降及长期生存率降低。Ikaros 在白血病发生和预后中的机制研究已成为人们关注的热点。     

Immunologic markers in childhood acute lymphoblastic leukemia

This article details the immunologic diversity of acute lymphoblastic leukemia in children. A historical review of developments in immunophenotyping is followed by a discussion of how major subgroups of leukemia are best defined today. The relationship of immunologic subtypes to stages of normal lymphoid development is explored, and the clinical impact of immunophenotyping is discussed.     

Glucocorticoid receptor in childhood acute lymphoblastic leukemia

Glucocorticoid(GC)hasbeenusedinthetreatmentofchildhoodacutelymphoblasticleukenda(ALL)formanyyears.IthasprovedthattheeffectofGCismediatedthroughaglucocortic0idreceptor(GCR)ofthetargetcell.[1]Therefore,manyexpertshaveconcentratdtheirattentiononGCR,butthereisnoreportonthestudyofGCRinchildho0dALLinChina.InununologicalclassificationofALLmaydifferentiatethecelloriginandclustersofdifferentiation(CD)inleukendacell.Itisoneoftheimportantindicatorstoguidecombinationchemotherapyandt0makeapr0gnos…     

Genetic susceptibility in childhood acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and a leading cause of death due to disease in children. The genetic basis of ALL susceptibility has been supported by its association with certain congenital disorders and, more recently, by several genome-wide association studies (GWAS). These GWAS identified common variants in ARID5B, IKZF1, CEBPE, CDKN2A, PIP4K2A, LHPP and ELK3 influencing ALL risk. However, the risk variants of these SNPs were not validated in all populations, suggesting that some of the loci could be population specific. On the other hand, the currently identified risk SNPs in these genes only account for 19% of the additive heritable risk. This estimation indicates that additional susceptibility variants could be discovered. In this review, we will provide an overview of the most important findings carried out in genetic susceptibility of childhood ALL in all GWAS and subsequent studies and we will also point to future directions that could be explored in the near future.     

Atopic disease and childhood acute lymphoblastic leukemia

Our objective was to test the hypothesis that the risk of childhood leukemia is associated with allergies or a family history of allergy. We used a German population-based case-control study with self-reported information on allergies of the children and their first-degree relatives. Our study included a total of 1,130 cases of acute lymphoblastic leukemia (ALL), 164 cases of acute myeloid leukemia (AML) and 2,957 controls. A major finding of our study is that hay fever, neurodermatitis and contact eczema are underrepresented within the group of children with ALL, with respective odds ratios (OR) of 0.45 (95% confidence interval [CI] 0.31-0.66) for hay fever, of 0.49 (CI 0.34-0.71) for neurodermatitis and of 0.62 (CI 0.39-0.99) for eczema, respectively. Atopic diseases, comprising hay fever, neurodermatitis and asthma, are much stronger related with a reduced risk of ALL than other allergies (OR 0.52, CI 0.40-0.67 vs. OR 0.89, CI 0.66-1.21). The strongest association is seen with an atopy in the index child; however, ALL risk is also reduced if one of the parents or a sibling had an atopic disease. No such consistent pattern is seen for AML. Our data suggest that atopy or a family history of atopy are associated with a reduced risk of childhood ALL. Recall bias remains a concern, but sensitivity analysis provided some evidence that the protective effect is unlikely to be attributable to this bias in its entirety.     

Skeletal morbidity in childhood acute lymphoblastic leukemia.

PURPOSE: Treatment for acute lymphoblastic leukemia (ALL) in childhood results in a reduction in bone mineral density (BMD). Whether there is a recovery of this lost bone mass in survivors of ALL is not known. We sought to determine if changes in BMD are common long-term sequelae in children with ALL. METHODS: Bone mineral densitometry of the lumbar spine and femoral neck was performed on 106 patients. The results were compared with those of age-matched normal controls. The effect of treatment was examined in those with low BMD compared with the remainder of the study group. RESULTS: When data were tested with respect to age, sex, and age and sex, no difference was observed in BMD between survivors of childhood ALL and controls. In the subgroup of patients with low BMD, the difference was not related to age, age at diagnosis, or years since diagnosis. Low BMD of the spine was not explained by radiotherapy (RT), methotrexate (MTX) dose, or corticosteroid dose. Low BMD of the femur was not explained by RT. However, those with low femoral BMD were more likely to have received high-dose MTX or higher-dose corticosteroids compared with the remainder of the group. CONCLUSION: It appears that survivors of childhood ALL as a whole recover normal BMD. However, those patients who received a total MTX dose of greater than 40000 mg/m(2) or a total corticosteroid dose of greater than 9000 mg/m(2) may not recover normal BMD and therefore should be screened for decreased BMD of the femoral neck.     

Late recurrence of childhood acute lymphoblastic leukemia

Late relapse of childhood lymphoblastic leukemia 10 years after the end of treatment is rare. A young woman whose acute lymphoblastic leukemia recurred 11 years after the end of treatment for acute lymphoblastic leukemia is described, and the literature on late relapse of childhood acute lymphoblastic leukemia is reviewed.     

Allelotype analysis in relapsed childhood acute lymphoblastic leukemia

We performed for the first time the allelotype of relapsed childhood acute lymphoblastic leukemia (ALL). A total of 38 cases were screened for loss of heterozygosity (LOH) using 71 markers. In all, 26 (68%) patients showed LOH on at least one chromosomal arm, indicating that LOH is a frequent event at relapse. The most frequent loss was found on chromosomal arm 9p at the p16/INK4a locus (39%). LOH at the TEL gene locus on chromosomal arm 12p also occurred often (25%). Frequent loss was observed on chromosome arms 4q (20%), 6q (21%), and 17q (20%). Sequential analysis (i.e. samples obtained from both initial diagnosis and relapse) shows that some patients (63%) have the identical LOH status at both phases, suggesting the presence of the same clone. Other samples (37%) showed distinct LOH alterations, indicating clonal evolution at relapse. Despite the heterogeneous and complex changes, some shared LOH loci occurred in these matched samples, suggesting that many of the same tumor-suppressor genes are aberrant at both phases. In summary, novel tumor-suppressor genes on chromosome arms 4q, 6q, and 17q, as well as the p16 and TEL genes, have an important role in the relapse of childhood ALL.     

Genetic susceptibility to childhood acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. The origin of this disease can be explained by a combination of genetic susceptibility factors and environmental exposures. For the purpose of our study it can be considered as a complex disease, caused by the "carcinogenic" effect of the environment modified by a series of genes. In population, these genes tend to occur in allelic forms representing functional polymorphisms thus explaining inter-individual variability in cancer susceptibility. The latter can be evaluated more realistically in childhood ALL than in sporadic cancers of the adult because of its relatively short latency period. We asked therefore, the question about the role of genes controlling the efficiency of xenobiotics metabolism in childhood leukemogenesis. Xenobiotics (drugs and carcinogens) are excreted from the body after metabolic conversion by enzymes mediating oxidation activation (Phase I) and conjugation detoxificaton (Phase II). Functional variants of these enzymes, resulting from known DNA polymorphisms in the corresponding genes, were shown to influence the risk to a variety of solid tumours in adults. A case-control study on ALL patients and healthy controls in a French-Canadian population was carried out by examining the loci of Phase I, CYP1A1 and CYP2D6, as well as Phase II enzymes, GSTM1, GSTT1, NAT1 and NAT2. The NAT2 slow-acetylator, CYP1A1*2A and GSTM1 null genotypes were shown to be significant risk determinants of ALL (OR=1.6, 1.8 and 1.8, respectively), whereas, polymorphisms in CYP2D6 and GSTT1 genes did not seem to play an important role in the aetiology of ALL. Interestingly, the risk associated with NAT2 slow-acetylators was most apparent among males homozygous for NAT1*4 (OR=3.3) whereas girls carrying the CYP1A1*4 allele were significantly underrepresented in the patient group (OR=0.2). These findings point to a gender-specific effect of DNA variants which, at least in part, may explain why ALL is more prevalent among boys. To assess gene-gene interactions, NAT2 slow-acetylators were considered together with GSTM1 null genotypes and CYP1A1*2A alleles. The combined presence of two risk-elevating genotypes appeared to confer an increased risk of ALL among the carriers (OR=2.6). This risk was increased further (OR=3.3) when all three genotypes occurred in the same individuals indicating that the combination of susceptibility variants is more predictive of risk then either of them independently. The association of leukemogenesis in children with metabolising gene variants suggests causal relation to environmental exposures.     

Spectral characteristics of acute lymphoblastic leukemia in childhood

Although the differentiation and classification of acute leukemia are based upon cytochemical features as well as immunologic, cytogenetic, and molecular characteristics, in many cases the morphological distinction of normal lymphocytes from lymphoblasts of acute lymphoblastic leukemia (ALL) is difficult using light microscopy. In this study the distinction between normal lymphocytes and lymphoblasts of childhood ALL is proposed using their spectral characteristics. The method has been based upon the analysis and classification of optical absorption characteristics of the bone marrow cells. Spectral microscopy system is capable of capturing a great number of narrow-band images, in the wide spectral range of the optical spectrum. The analysis showed statistically significant difference (P < 0.0001) between normal lymphocytes and lymphoblasts as far as it concerns the detection, identification and mapping of their spectral absorption characteristics. Our results suggest the potential of spectral imaging as a new method for the distinction of lymphocytes from lymphoblasts in cases that with the light microscope, the morphologic differences are not visible in the bone marrow smears at diagnosis or the follow up of the children with ALL.     

Induction failure in acute lymphoblastic leukemia of childhood

BACKGROUND: Although it is widely accepted that failure to achieve complete remission (CR) portends a poor prognosis in childhood acute lymphoblastic leukemia (ALL), there is variability in the precise definition of induction failure and, to the authors' knowledge, few published data exist regarding the outcome of patients who are slow to achieve CR. METHODS: Between 1987-1995, 774 children with ALL were treated on 2 consecutive protocols and were evaluable to assess the time required to attain CR. The authors compared presenting characteristics and outcomes of patients based on their remission status after 1 month of induction chemotherapy: CR (n = 656), protracted hypoplasia (low peripheral blood counts and/or hypocellular marrow) (n = 95), and persistent leukemia (M2 or M3 bone marrow and/or evidence of extramedullary leukemia) (n = 23). The median follow-up was 5.2 years. RESULTS: Presenting features that predicted persistent leukemia included a leukocyte count > 100,000/mm3 and T-cell phenotype. Approximately 91% of patients with persistent leukemia and 100% with protracted hypoplasia eventually achieved CR. The 5-year event free survival (EFS) (95% confidence intervals [95% CI] in parentheses) for patients with persistent leukemia after 1 month was 16% (95% CI, 0%, 31%), which was significantly worse (P < 0.001) than that for those who achieved CR within 1 month (5-year EFS, 82%; 95% CI, 79%, 86%) and that for those with protracted hypoplasia (5-year EFS, 79%; 95% CI, 70%, 87%). For patients with persistent leukemia, there was no significant difference in survival based on bone marrow status (M2 or M3) after 1 month or on the number of induction cycles received before achieving CR. CONCLUSIONS: Patients with persistent leukemia at the end of 1 month of therapy have a dismal prognosis, regardless of when they subsequently achieve CR. More intensive and/or novel therapies should be considered for this subset of patients.     

Clinical trials with daunorubincin-DNA and adriamycin-DNA in acute lymphoblastic leukemia of childhood,acute nonlymphoblastic leukemia,and bronchogenic carcinoma

Summary Treatment with daunorubicin-DNA (DNR-DNA) or adriamycin-DNA (ADM-DNA) has been evaluated in acute lymphoblastic leukemia of childhood (ALL), acute nonlymphoblastic leukemia (ANLL) and bronchogenic carcinoma (BC). The Five-year survival rate in 69 children with ALL was 73.7% when ADM-DNA was introduced in the treatment and 38% with DNR-DNA (P=0.03).A randomization between free DNR and DNR-DNA for remission induction in 26 patients with ANLL has shown that the drugs were of equivalent effectiveness. The one-year survival rate was 66% for the DNR group and 64% for the DNR-DNA group.In 59 patients with BC, a randomized trial between ADM-DNA and cyclophosphamide-vinblastine (CTX-VLB) did not show an advantage infavor of one of these treatments. In anaplastic BC (51 patients), there was no difference in survival rate or remission rate between patients treated with ADM or ADM-DNA.No cardiotoxicity was noted among the patients treated with the complexed drugs. ADM-DNA and DNR-DNA are as effective as the free drugs. Cardiotoxicity appears to be reduced.Aspirant du Fonds National de la Recherche Scientifique de Belgique     

Resistance-related proteins in initial and relapsed childhood acute lymphoblastic leukemia

One hundred and eleven children with initial ALL and 28 children with relapsed ALL were analyzed immunohistochemically for expression of resistance-related proteins. P-glycoprotein (P-170) was found in 35% (initial ALL) vs 54% (relapsed ALL; p=0.07), glutathione S-transferase-pi (GST) in 49% vs 68% (p=0.07), thymidylate-synthase (TS) in 42% vs 64% (p=0.03), dihydrofolate-reductase (DHFR) in 20% vs 32% and metallothionein (MT) in 33% vs 32% of the cases. In initial ALL, the resistance proteins P-170 and GST were expressed more frequently in patients who relapsed under therapy and the frequency was similar to relapsed ALL. These results indicate that P-170 and GST-pi were already present before treatment. In contrast, expression of TS increased during treatment.     

TP53 alterations in relapsed childhood acute lymphoblastic leukemia

TP53 alterations are frequent relapse‐acquired mutations in childhood acute lymphoblastic leukemia (ALL). The present study evaluated the clinical significance of relapsed childhood ALL in Taiwan. Diagnostic and/or relapsed bone marrow or peripheral blood was obtained from 111 children with relapsed ALL who were initially treated by using Taiwan Pediatric Oncology Group (TPOG) ALL protocols from January 1997 to May 2018. Mutations were detected by PCR and sequencing, as well as by multiplex ligation‐dependent probe amplification to detect copy number alterations. Copy number and/or sequence alterations of TP53 were detected in 29% (28 of 98) and in 46% (6 of 13) of patients with relapsed B‐cell and T‐cell ALL, respectively. This incidence was much higher than that in several similar studies conducted in Caucasian populations. Seventy percent of all TP53 alterations were gained at relapse in 67 matched samples by back‐tracking matched diagnostic samples. TP53 alterations were associated with lower 5‐year event‐free survival (EFS) and overall survival (OS) rates (P = .013 and P = .0002, respectively). Multivariate analysis confirmed the prognostic significance of TP53 alterations. Forty‐five patients received hematopoietic stem‐cell transplantations post‐relapse. Patients with TP53 alterations (14/45) had inferior 5‐year EFS and OS than patients without TP53 alterations after transplantation (P = .002 and P = .001, respectively). The significance of these TP53 alterations for patients who received transplantations was confirmed by multivariate analysis. In conclusion, TP53 alterations were enriched and useful as prognostic markers in relapsed childhood ALL.     

The prenatal origin of childhood acute lymphoblastic leukemia

Until recently, the etiology of childhood acute lymphoblastic leukemia (ALL) has remained relatively elusive. Several studies have established a time frame for the development of ALL which could lead to the identification of specific exposures linked to leukemogenesis from the generation of the initial leukemic clone until clinical diagnosis. Utilizing newborn screening ('Guthrie') cards, leukemic clones have been detected retrospectively in dried blood spots using two different PCR-based approaches: (i) the amplification of patient/leukemia-specific breakpoint fusion sequences of rearranged oncogenes; and (ii) the amplification of clonal immunoglobulin heavy chain gene (IgH) or T cell receptor (TcR) gene rearrangements. These studies support the hypothesis that a large proportion of childhood ALL cases arise in utero. In several studies, a long latency period from the generation in utero of the initial ALL clone to clinical diagnosis, indicates that additional genetic events are required for the full development of the leukemia phenotype, potentially from postnatal exposures (e.g. infections). The identification of leukemia-associated translocations in umbilical cord blood samples of healthy newborns, suggest that in the future children may be identified prospectively who have an increased risk of developing leukemia.     

Deregulated WNT signaling in childhood T-cell acute lymphoblastic leukemia

WNT signaling has been implicated in the regulation of hematopoietic stem cells and plays an important role during T-cell development in thymus. Here we investigated WNT pathway activation in childhood T-cell acute lymphoblastic leukemia (T-ALL) patients. To evaluate the potential role of WNT signaling in T-cell leukomogenesis, we performed expression analysis of key components of WNT pathway. More than 85% of the childhood T-ALL patients showed upregulated β-catenin expression at the protein level compared with normal human thymocytes. The impact of this upregulation was reflected in high expression of known target genes (AXIN2, c-MYC, TCF1 and LEF). Especially AXIN2, the universal target gene of WNT pathway, was upregulated at both mRNA and protein levels in ∼40% of the patients. When β-CATENIN gene was silenced by small interfering RNA, the cancer cells showed higher rates of apoptosis. These results demonstrate that abnormal WNT signaling activation occurs in a significant fraction of human T-ALL cases independent of known T-ALL risk factors. We conclude that deregulated WNT signaling is a novel oncogenic event in childhood T-ALL.     

Bone marrow necrosis preceding acute lymphoblastic leukemia in childhood

Two patients who presented with bone marrow necrosis and eventually developed acute lymphocytic leukemia are reported, and similar cases in the literature are reviewed. Both patients responded to chemotherapy. Several possible mechanisms are discussed. Bone marrow necrosis appears to be another condition preceding acute lymphocytic leukemia in children.     

Recent advance in treatment of childhood acute lymphoblastic leukemia

The five-year event-free survival of nearly 80% in childhood acute lymphoblastic leukemia (ALL) achieved in the 1990 s attested to the effectiveness of risk-directed therapy developed through well-designed clinical trials by 4 groups in clinical study, containing CCLSG, TCCSG, KYCCSG and JACLS. Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) was organized in 2003 and includes all four clinical study groups in Japan. For the purpose of finding the standard treatment, JPLSG protocols have been started for three distinct and rare types of ALL, including mature B-ALL, infant ALL and Ph+ALL. The 2004 ALL protocol of Childhood Cancer and Leukemia Group in Japan (CCLSG) contained a new 2-step stratification based on initial age/WBC count and minimal residual disease at day 91. The JPLSG/ALL committee was started in 2005 for discussing the ongoing need for cooperative clinical study in Japan and the possibility of nelarabine-containing regimen for T-ALL.     

Further heterogeneity of childhood common acute lymphoblastic leukemia

In an attempt to look further at the problem of heterogeneity, we have studied the immunoglobulin (Ig) gene organization in leukemic cells from 20 children with acute lymphoblastic leukemia (common ALL). Nineteen cases were divided into two subgroups: 12 cases with rearrangement of the Ig heavy (H) chain genes and 7 cases with rearrangement of both the Ig H and light (L) chain genes. No Ig gene rearrangement was found in one case. These findings indicate that there is more heterogeneity among patients with common ALL than has previously been believed.