Pegaspargase induced multiple organ failure with acute lymphoblastic leukemia:A case report

BACKGROUND The introduction of pegaspargase has greatly advanced the treatment of acute lymphoblastic leukemia(ALL).In the literature,only one case of pegaspargaseinduced multiple organ failure has been reported,and the patient died due to multiple organ failure.CASE SUMMARY Herein,we present a rare case of a 40-year-old man with ALL who developed multiple organ failure after treatment with pegaspargase.The patient had two rare phenomena reflecting poor prognosis,including the discrepancy between clinical manifestations and liver function and persistently low alpha-fetoprotein(AFP)levels from subacute liver failure.However,the patient was successfully treated using a multidisciplinary team approach.CONCLUSION This is the first case report of successful treatment of pegaspargase-induced multiple organ failure.The findings emphasize the importance of a multidisciplinary team approach in treating pegaspargase-induced multiple organ failure.

Deep Learning and Artificial Intelligence-Driven Advanced Methods for Acute Lymphoblastic Leukemia Identification and Classification: A Systematic Review

Automatic detection of Leukemia or blood cancer is one of the most challenging tasks that need to be addressed in the healthcare system.Analysis of white blood cells(WBCs)in the blood or bone marrow microscopic slide images play a crucial part in early identification to facilitate medical experts.For Acute Lymphocytic Leukemia(ALL),the most preferred part of the blood or marrow is to be analyzed by the experts before it spreads in the whole body and the condition becomes worse.The researchers have done a lot of work in this field,to demonstrate a comprehensive analysis few literature reviews have been published focusing on various artificial intelligence-based techniques like machine and deep learning detection of ALL.The systematic review has been done in this article under the PRISMA guidelines which presents the most recent advancements in this field.Different image segmentation techniques were broadly studied and categorized from various online databases like Google Scholar,Science Direct,and PubMed as image processing-based,traditional machine and deep learning-based,and advanced deep learning-based models were presented.Convolutional Neural Networks(CNN)based on traditional models and then the recent advancements in CNN used for the classification of ALL into its subtypes.A critical analysis of the existing methods is provided to offer clarity on the current state of the field.Finally,the paper concludes with insights and suggestions for future research,aiming to guide new researchers in the development of advanced automated systems for detecting life-threatening diseases.

Novel PIKfyve/Tubulin Dual-target Inhibitor as a Promising Therapeutic Strategy for B-cell Acute Lymphoblastic Leukemia

Objective:In B-cell acute lymphoblastic leukemia(B-ALL),current intensive chemotherapies for adult patients fail to achieve durable responses in more than 50%of cases,underscoring the urgent need for new therapeutic regimens for this patient population.The present study aimed to determine whether HZX-02-059,a novel dual-target inhibitor targeting both phosphatidylinositol-3-phosphate 5-kinase(PIKfyve)and tubulin,is lethal to B-ALL cells and is a potential therapeutic for B-ALL patients.Methods:Cell proliferation,vacuolization,apoptosis,cell cycle,and in-vivo tumor growth were evaluated.In addition,Genome-wide RNA-sequencing studies were conducted to elucidate the mechanisms of action underlying the anti-leukemia activity of HZX-02-059 in B-ALL.Results:HZX-02-059 was found to inhibit cell proliferation,induce vacuolization,promote apoptosis,block the cell cycle,and reduce in-vivo tumor growth.Downregulation of the p53 pathway and suppression of the phosphoinositide 3-kinase(PI3K)/AKT pathway and the downstream transcription factors c-Myc and NF-κB were responsible for these observations.Conclusion:Overall,these findings suggest that HZX-02-059 is a promising agent for the treatment of B-ALL patients resistant to conventional therapies.

Damage Mechanism of CK2 and IKAROS in Philadelphia Like Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is characterized by immature and poorly differentiated B lymphocytes in large numbers in the blood. B cells are distinct from the cell types involved in their development (common lymphoid progenitor cells, pro-B cells, pre-B cells, and mature cells). The process of B cell maturation depends on precise communication within the cell: signals activate specific genes that are essential for proper development. Errors in this intricate signaling network can lead to issues with B cell function and contribute to disease. B-lineage acute lymphoid leukemias, malignancies of precursor-stage B lymphoid cells inhibit lymphoid differentiation, leading to abnormal cell proliferation and survival. The process of developing leukemia (leukemogenesis) can be triggered by an overproduction of both hematopoietic stem cells (the cells that form all blood cells) and the immature versions of white blood cells called lymphoblasts. Acute lymphoblastic leukemia (ALL) with the presence of the Philadelphia chromosome (ALL Ph) is classified as a high-risk manifestation of the disease, this chromosome is the product of the reciprocal translocation, whose product is a BCR-ABL fusion protein. It is a highly active tyrosine kinase that can transform hematopoietic cells into cytokine-independent. Hyperphosphorylation cascades inhibit the differentiating function of IKZF1 as a tumor suppressor gene which leads to an abnormal proliferation of B cells due to the presence of the Philadelphia chromosome;it inhibits the differentiating process, leukemogenesis involving immature B cells in the bloodstream can result from the uncontrolled growth and division of hematopoietic stem cells and immature lymphoblasts (the precursors to B cells).

Osteoarticular Manifestations of Pediatric Acute Lymphoblastic Leukemia: Study of an Observation and Review of the Literature

Introduction: Acute lymphoblastic leukemia (ALL) is a monoclonal hematological malignancy characterized by infiltration of the bone marrow by more than 20% of hematopoietic cells with blocked differentiation, called blasts, belonging to the lymphoblastic lineage of lymphoid nature (B or T lymphoblasts). Around 40% of childhood cancers are leukemias, and 85% of these are ALL. The first descriptions of osteoarticular involvement as an inaugural manifestation date back to 1913 with August Strauch. Our aim was to describe an isolated case of ALL with osteoarticular manifestations as an inaugural event supported by a review of the literature. Observation: A 14-year-old adolescent with no known pathological history was referred from pediatrics to investigate the etiology of a chronic peripheral polyarthritis that had been progressively evolving for about seven weeks. Clinically, he presented with chronic peripheral polyarthritis, polysynovitis, non-ankylosing deforming involving knees, shoulders, wrists, and proximal interphalangeals (PIP), and a leukemic facies (facial puffiness and periorbital erythema). Biological investigations revealed a non-specific inflammatory syndrome with a VS of 60 mm in the first hour and CRP increased to 45 mg/l (N ≤ 6 mg/l). The blood count showed hyperleukocytosis at 25,600/mm3 with lymphocyte predominance at 18,660/mm3, normocytic normochromic anemia with hemoglobin at 11 g/dl, and hyperplakettosis at 510,000/mm3. The blood smear showed 37% blasts confirmed on the medullogram, with more than 20% blastic invasion and a predominance of common B-type lymphocytes on immunophenotyping with negative Philadelphia. Immunological, renal, infectious, hepatic, lipid, and uricemia tests were normal. These clinical and paraclinical findings led to the diagnosis of B-type lymphocytic leukemia. The patient received multidrug therapy for induction, consolidation, and intensification. As part of the management of his osteoarticular disorders, infiltrations of the large painful joints were carried out with an adequate phosphocalcic intake. Conclusion: Leukemia is a diagnostic and therapeutic emergency, and osteoarticular damage may be the initial presentation.

Myelodysplastic syndrome transformed into B-lineage acute lymphoblastic leukemia: A case report

BACKGROUND Myelodysplastic syndromes(MDSs)are a group of hematological diseases caused by expansion of an abnormal clone of hematopoietic stem cells.Primary MDS is a potentially premalignant clonal disorder that may progress to overt acute leukemia in 25%-50%of cases.However,most of these cases evolve into acute myeloid leukemia and rarely progress to acute lymphoblastic leukemia(ALL).Thus,transformation of MDS into B-cell ALL is rare.CASE SUMMARY A 58-year-old man was admitted to the hospital for reduced blood cell counts.Based on all the test results and the World Health Organization diagnosis and classification,the patient was finally diagnosed with ring-shaped sideroblastic MDS with refractory hemocytopenia due to multilineage dysplasia.We used red blood cell transfusions and other symptomatic support treatments.After 4 years,the patient felt dizziness,fatigue,and night sweats.We improved bone marrow and peripheral blood and other related auxiliary examinations.He was eventually diagnosed with B-lineage acute lymphocytic leukemia(MDS transformation).CONCLUSION The number of peripheral blood cells,type of MDS,proportion of primitive cells in bone marrow,and number and quality of karyotypes are all closely related to the conversion of MDS to ALL.

Resveratrol Induces Apoptosis and Autophagy in T-cell Acute Lymphoblastic Leukemia Cells by Inhibiting Akt/mTOR and Activating p38-MAPK

Objective To explore the effects of resveratrol-induced apoptosis and autophagy in T-cell acute lymphoblastic leukemia （T-ALL） cells and potential molecular mechanisms. Methods The anti-proliferation effect of resveratrol-induced, apoptosis and autophagy on T-ALL cells were detected by using MTI- test, immunofluorescence, electronic microscope, and flow cytometry, respectively. Western blotting was performed for detecting changes of apoptosis-associated proteins, cell cycle regulatory proteins and state of activation of Akt, mTOR, p70S6K, 4E-BP1, and p38-MAPK. Results Resveratrol inhibited the proliferation and dose and time-dependent manner. It also induced cyclin-dependent kinase （CDK） inhibitors p21 and induced apoptosis and autophagy in T-ALL cells in a cell cycle arrest at G0/G1 phase via up regulating p27 and down regulating cyclin A and cyclin D1. Western blotting revealed that resveratrol significantly decreased the expression of antiapoptotic proteins （Mcl-1 and Bcl-2） and increased the expression of proapoptotic proteins （Bax, Bim, and Bad）, and induced cleaved-caspase-3 in a time-dependent manner. Significant increase in ratio of LC3-11/LC3-1 and Beclin 1 was also detected. Furthermore, resveratrol induced significant dephosphorylation of Akt, mTOR, p70S6K, and 4E-BP1, but enhanced specific phosphorylation of p38-MAPK which could be blocked by SB203580. When autophagy was suppressed by 3-MA, apoptosis in T-ALL cells induced by resveratrol was enhanced. Conclusion Our findings have suggested that resveratrol induces cell cycle arrest, apoptosis, and autophagy in T-ALL cells through inhibiting Akt/mTOR/p7OS6K/4E-BP1 and activating p38-MAPK signaling pathways. Autophagy might play a role as a self-defense mechanism in T-ALL cells treated by resveratrol. Therefore, the reasonable inhibition of autophagy in T-ALL cells may serve as a promising strategy for resveratrol induced apoptosis and can be used as adjuvant chemotherapy for T-ALL.

The Characteristics of Immunophenotype in Acute Lymphoblastic Leukemia and Its Clinical Significance

Objective： To study the characteristics of immunophenotype in acute lymphoblastic leukemia （ALL） and its clinical significance. Methods： Immunophenotyping was performed on 81 ALL patients by three-color flow cytometry analysis using CD45/SSC gating, meanwhile the cytogenetic analysis was performed on 45 cases out of 81 ALL patients. Results： （1） CD19 was the most commonly expressed of all B-lineage antigens detected with the positive rate being 100%. In T-ALL, the positive expression rate of CD5 and CD7 was the highest, being 90%. Both B-ALL and T-ALL overlapped in expression of lineage antigens. There was no significant difference in the complete remission rate （CR rate） between T-ALL and B-ALL. （2） The incidence of ALL with rayeloid antigens expression （My＋ALL） was 39.5%. CD13 was most often seen among the myeloid markers. My＋ALL always involved in B-lineage antigens and the CR rate in children and adults was 72.2% and 78.6% respectively. （3） The incidence of HAL was 19.8%. Coexpression of B-lineage and myeloid-assoeiated antigens was the commonest subtype in HAL. The expression of CD34 was commonly seen in HAL patients （81.3%）. The CR rate was low in HAL, 50% for children and 40% for adults. （4） Compared to T-ALL, B-ALL, My＋ALL, and HAL had a higher positive rate of CD34 expression with the difference being significant （P〈0.025）. Conclusion： Immunophenotyping had remarkable predominance in diagnosing special category of ALL （such as HAL and My＋ALL）; CD19 and CD5 were highly sensitive in diagnosing B-ALL and T-ALL, but less special, and overlapping was found in expression. No significant association was found between the expression of CD34 or myeloid antigens and CR rate, while low CR rate was found in HAL patients, especially for those coexpressing CD34 antigen.

Establishment of Reproducible Xenotransplantation Model of T Cell Acute Lymphoblastic Leukemia in NOD/SCID Mice

T cell acute lymphoblastic leukemia(T-ALL) is an aggressive leukemia.However the poor prognosis and low morbidity restrict further analysis of the disease.Therefore there is an increasing demand to develop animal models for identifying novel therapeutic approaches.In this study,we inoculated the anti-mouse CD122 monoclonal antibody conditioned NOD/SCID mice with the leukemia cells from 9 T-ALL patients and 1 cell line via the tail vein.Four of the 9 patients and the cell line were successfully engrafted.Flow cytometry detected high percentage of human CD45 + cells in recipient mice.Immunohistochemistry showed infiltration of human CD45 + cells in different organs.Serial transplantation was also achieved.In vivo drug treatment showed that dexamethasone could extend survival,which was consistent with clinical observation.These results demonstrated that we successfully established 5 xenotransplantation models of T-ALL in anti-mCD122 mAb conditioned NOD/SCID mice,which recapitulated the characteristics of original disease.

MicroRNA-145-3p suppresses the malignant behaviors of T-cell acute lymphoblastic leukemia Jurkat cells via inhibiting the NF-kappaB signaling pathway

T-cell acute lymphoblastic leukemia(T-ALL)is a hematological tumor caused by the malignant transformation of immature T-cell progenitor cells.Emerging studies have stated that microRNAs(miRNAs)may play key roles in T-ALL progression.This study aimed to investigate the roles of miR-145-3p in T-ALL cell proliferation,invasion,and apoptosis with the involvement of the nuclear factor-kappaB(NF-κB)signaling pathway.T-ALL Jurkat cells were harvested,and the expression of miR-145-3p and NF-κB-p65 was measured.Gain-and loss-of-functions of miR-145-3p and NF-κB-p65 were performed to identify their roles in the biological behaviors of Jurkat cells,including proliferation,apoptosis,and invasion.Consequently,the current study demonstrated that miR-145-3p was down-regulated while NF-κB-p65 was up-regulated in Jurkat cells.miR-145-3p directly bound to the 3’untranslated region of NF-κB-p65.Over-expression of miR-145-3p inhibited Jurkat cell proliferation,invasion,and resistance to apoptosis,while over-expression of NF-κB-p65 presented opposite trends.Co-transfection of miR-145-3p and NF-κB-p65 promoted the malignant behaviors of Jurkat cells compared to miR-145-3p transfection alone,while it reduced these behaviors of Jurkat cells compared to NF-κB-p65 transfection alone.Taken together,this study provided evidence that miR-145-3p could suppress proliferation,invasion,and resistance to the death of T-ALL cells via inactivating the NF-κB signaling pathway.

Predictive Value of Dynamic Peri-Transplantation MRD Assessed By MFC Either Alone or in Combination with Other Variables for Outcomes of Patients with T-Cell Acute Lymphoblastic Leukemia

We performed a retrospective analysis to investigate dynamic peri-hematopoieticstem cell transplantation(HSCT)minimal/measurable residual disease(MRD)on outcomes inpatients with T-cell acute lymphoblastic leukemia(T-ALL).A total of 271 patients were enrolledand classified into three groups:unchanged ncgative MRD pre-and post-HSCT group(group A),post-MRD non-increase group(group B),and post-MRD increase group(group C).The patientsin group B and group C experienced a higher cumulative incidence of relapse(CIR)(42%vs.71%vs.16%,P<0.001)and lower leukemia-free survival(LFS)(46%vs.21%vs.70%,P<0.001)andoverall survival(OS)(50%vs.28%vs.72%,P<0.001)than in group A,but there was no significantdifference in non-relapse mortality(NRM)among three groups(14%vs.12%vs.8%,P=0.752).Multivariate analysis showed that dynamic peri-HSCT MRD was associated with CIR(HR=2.392,95%CI,1.816-3.151,P<0.001),LFS(HR=1.964,95%CI,1.546-2.496,P<0.001)and os(HR=1.731,95%CI,1.348-2.222,P<0.001).We also established a risk scoring system based ondynamic peri-HSCT MRD combined with remission status pre-HSCT and onsct of chronic graft-versus-host disease(GVHD).This risk scoring system could better distinguish ClR(c=0.730)thanthat for pre-HSCT MRD(c=0.562),post-HSCT MRD(c=0.616)and pre-and post-MRD dynamics(c=0.648).Our results confirm the outcome predictive value of dynamic peri-HSCT MRD eitheralone or in combination with other variables for patients with T-ALL.

Diphtheria Toxin/Human B-Cell Activating Factor Fusion Protein Kills Human Acute Lymphoblastic Leukemia BALL-1 Cells: An Experimental Study

Objective： This study aimed to express a fusion protein of diphtheria toxin and human B cell-activating factor （DT388sBAFF） in Escherichia coli （E. coli） and investigate its activity in human B-lineage acute lymphoblastic leukemia 1 cells （BALL-1）. Methods： A fragment of DT388sBAFF fusion gene was separated from plasmid pUC57-DT388sBAFF digested with Nde I and Xho I, and inserted into the expression vector pcold II digested with the same enzymes. Recombinants were screened by the colony polymerase chain reaction （PCR） and restriction map. The recombinant expression vector was transformed into BL21 and its expression was induced by isopropyl β-D-1-thiogalactopyranoside （IPTG）. The recombinant protein was identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis （SDS-PAGE） and Western blot, and then purified by Ni2＋-NTA affinity chromatography. The expression level of B cell-activating factor receptor （BAFF-R） on BALL-1 cells was assessed by real-time PCR. The receptor binding capacity of recombinant protein was determined by cell fluorescent assay. The specific cytotoxicity of recombinant protein on BALL-1 cells was detected by 3-（4,5-dimethylthiazolyl-2）-2,5-diphenyltetrazolium bromide （MTT） assay. Results： The expression level of recombinant protein was 50% of total bacterial proteins in E. coli, and the recombinant protein could bind to BAFF-R-positive BALL-1 cells and thereby produce a cytotoxic effect on the cells. Conclusion： The fusion protein expression vector DT388sBAFF was successfully constructed and the recombinant protein with selective cytotoxicity against BALL-1 cells was obtained, providing foundation for further study of the therapy of human B-lineage acute lymphoblastic leukemia.

Primary isolated central nervous system acute lymphoblastic leukemia with BCR-ABL1 rearrangement:A case report

BACKGROUND BCR-ABL1 fusion gene is associated with a poor prognosis and a high incidence in central nervous system(CNS)leukemia.CNS invasion which detected at the initial diagnosis is commonly with bone marrow infiltration.It is uncommon for the leukemia cells to be located primarily in the CNS without bone marrow involvement.CASE SUMMARY We here report the rare initial presentation of CNS-restricted BCR-ABL-positive acute lymphoblastic leukemia in a 30-year-old female patient who clinically manifested with leukemic meningitis,with no involvement in peripheral blood or bone marrow.Identification of abnormal phenotypes of blast cells,and BCR-ABL1 rearrangement in the cerebrospinal fluid alone established the diagnosis of primary CNS-isolated acute lymphocytic leukemia.The patient received a combination of intrathecal therapy and high-dose chemotherapy.But the benefits of the treatments were short-lived and she experienced recurrence.CONCLUSION Flow cytometry in combination with molecular genetic analysis improved diagnostic accuracy.New approaches that may enhance the efficacy of the existing therapies and cure CNS leukemia are required.

The Role of Mitochondrial VDAC2 in the Survival and Proliferation of T-Cell Acute Lymphoblastic Leukemia Cells

Background: T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematological malignancy with aberrant T-cell developmental arrest. Individuals with relapsed T-ALL have limited therapeutic alternatives and poor prognosis. The mitochondrial function is critical for the T-cell viability. The voltage-dependent anion channel 2 (VDAC2) in the mitochondrial outer membrane, interacts with pro-apoptotic BCL-2 proteins and mediates the apoptosis of several cancer cell lines. Objective: The aim of the current study is to explore the role of VDAC2 in T-ALL cell survival and proliferation. Methods: Publicly available datasets of RNA-seq results were analyzed for expression of VDAC isoforms and T-ALL cell lines were treated with a VDAC2 small molecular inhibitor erastin. A VDAC2 RNA interference (siRNA) was delivered to T-ALL cell lines using a retroviral vector. Functional assays were performed to investigate the VDAC2 siRNA impacts on cell proliferation, apoptosis and survival of T-ALL cells. Results: Our analysis found a high expression of VDAC2 mRNA in various T-ALL cell lines. Public datasets of T-ALL RNA-seq also showed that VDAC2 is highly expressed in T-ALL (116.2 ± 36.7), compared to control groups. Only two T-ALL cell lines showed sensitivity to erastin (20 μM) after 48 hours of incubation, including Jurkat (IC50 = 3.943 μM) and Molt4 (IC50 = 3.286 μM), while another two T-ALL cells (CUTLL1 and RPMI 8402) had unstable IC50. However, five T-ALL cell lines (LOUCY, CCRF-CEM, P12-ICHI, HPB-ALL, and PEER cells) showed resistance to erastin. On the contrary, all T-ALL cell lines genetically inhibited with VDAC2 siRNA led to more than 80% decrease in VDAC2 mRNA levels, and a Conclusion: VDAC2 is highly expressed in T-ALL cells. The inhibition of VDAC2 significantly decreased cell viability, increased apoptosis, reduced cell proliferation and caused cell cycle sub-G1 arrest of T-ALL cells.

Decitabine for Relapsed Acute Lymphoblastic Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

Relapse after allogeneic hematopoietic stem cell transplantation（allo-HSCT） remains a main question on treatment failure. Current strategies for management that usually include salvage chemotherapy, donor lymphocytic infusion and second transplantation. Our study assessed the efficacy of decitabine（DAC） for treating patients with acute lymphoblastic leukemia（ALL） who relapsed after allogeneic hematopoietic stem cell transplantation（allo-HSCT）. We retrospectively analyzed the outcomes of 12 patients with relapsed ALL after allo-HSCT who received DAC therapy. Nine patients received DAC combined with chemotherapy and donor stem cell infusion, and 3 patients received single-agent DAC. Ten of the 12 patients achieved complete remission（CR）, 1 achieved a partial remission（PR）, and 1 had no response（NR） after treatment at the latest follow-up（LFU）, the median survival was 11.2 months（range, 3.8–34, 7 months）. The 1-and 2-year overall survival（OS） rates were 50%（6/12） and 25%（3/12）, respectively. Five patients were still alive; 4 had maintained CR and 1 was alive with disease. Patients with Philadelphia chromosome-positive ALL had higher survival rate than patients with Philadelphia chromosome-negative ALL（57.1% vs. 20%）. No aggravated flares of graft-versus-host disease（GVHD） were observed during DAC treatment. Therefore, DAC may be a promising therapeutic agent for ALL recurrence after allo-HSCT.

Rapamycin Sensitizes Glucocorticoid Resistant Acute Lymphoblastic Leukemia CEM-C1 Cells to Dexamethasone Induced Apoptosis through both mTOR Suppression and Up-Regulation and Activation of Glucocorticoid Receptor

Objective To explore the role of glucocorticoid （GC） receptor （GR） in rapamycin＇s reversion of GC resistance in humanGC-resistant T-acute lymphoblastic leukemia （ALL） CEM-C1 cells. Methods CEM-C1 cells were cultured in vitro and treated with rapamycin at different concentrations with or without 1 μmol/L dexamethasone （Dex）. 3-（4, 5-dimethylthiazol-2-yl）-2, 5-diphenyltetrazolium bromide （MTT） test was performed to assess cell proliferation. The cell cycle and cell apoptosis were analyzed by flow cytometry. The expression of GRα mRNA was determined by real-time quantitative RT-PCR. The expression of GR, p-70S6K, Mcl-1, and Bim proteins was detected by Western blot. Results When incubated with rapamycin at different concentrations, CEM-C1 cells showed significant growth inhibition in a time- and concentration-dependent manner. The growth inhibition was synergistically increased when CEM-C1 cells were treated with rapamycin plus 1 μmol/L Dex. CEM-C1 cells treated with rapamycin alone showed no apparent apoptosis, and were arrested at G0/G1 phase. After the treatment with Dex plus rapamycin, CEM-C1 cells demonstrated apparent apoptosis and increased the cell cycle arrested at G0/G1 phase. Rapamycin combined with Dex up-regulated GRα, phosphorylated GR（p-GR）, and pro-apoptotic protein Bim-EL in CEM-C1 cells, but inhibited the expression of p-p70S6K, a downstream target protein ofmTOR （mammalian target of rapamycin）. Conclusion After the treatment with rapamycin plus Dex, Dex resistant CEM-C1 cells induce growth inhibition and apoptosis. The underlying mechanism may involve inhibition of the mTOR signaling pathway and also be associated with up-regulation of GR expression and activation of GC-GR signaling pathway.

DNA repair gene XRCC1 polymorphisms and susceptibility to childhood acute lymphoblastic leukemia: a meta-analysis

Objective： To estimate the relationship between genetic polymorphisms of X-ray repair cross- complementing group 1 （XRCC1） and the susceptibility to childhood acute lymphoblastic leukemia （ALL）. Methods： Relevant case-control studies were enrolled in the meta-analysis. We applied Rev Man 4.2 software to pool raw data and test studies＇ heterogeneity and to calculate the incorporated odds ratio （OR） and 95% confidence interval （95% CI）. Results： Our data showed that the OR for the Gln allele of the Arg399Gln polymorphism, compared with the Arg allele, was 1.35 （95% CI, 1.16-1.57; P〈0.0001） for childhood ALL patients. Similarly, the homozygous genotype Gln/Gln and heterozygous genotype Arg/Gln both significantly increased the risk of childhood ALL compared with the wild genotype Arg/Arg （OR =1.58; 95% CI, 1.13-2.21; P=0.008; OR =1.51; 95% CI, 1.21-1.87; P=0.0002）. The dominant model of Arg399Gln was associated with childhood ALL risk （OR =1.54; 95% CI, 1.25-1.89; P〈0.0001）. The ethnic subgroup analysis demonstrated that the Gln allele in all five ethnic groups was prone to be a risk factor for childhood ALL just with different degrees of correlation while Arg194Trp SNP showed a protective or risk factor or irrelevant thing in different races. Conclusions： XRCC1 399 polymorphism may increase the risk of childhood ALL. Different ethnic groups with some gene polymorphism have different disease risks.

Arsenic Trioxide Induces Apoptosis of Glucocorticoid-Resistant Acute Lymphoblastic Leukemia CEM-C1 Cells

Objective： To explore the effects of arsenic trioxide （ATO） on the apoptosis of glucocorticoid （GC）-resistant T-acute lymphoblastic leukemia （ALL） CEM-C1 cells and its possible mechanisms. Methods： Different concentrations of ATO （0.25 μmol/L-5 μmol/L） were used to induce the apoptosis of CEM-C1 cells. The inhibition rate of cell proliferation and apoptosis were detected by MTT test, Annexin V-FITC/PI flow cytometry and optical microscopy, respectively. RT-PCR was applied to semi-quantitatively analyze the mRNA expression of pro-apoptotic proteins （Bad and PDCD4） and anti-apoptotic proteins （XIAP and MCL-1） induced by different concentrations of ATO at different time points. Results： ATO could inhibit proliferation and induce apoptosis of CEM-C1 cells at a concentration and time dependent manner. Low-dose ATO mildly inhibited the proliferation of CEM-C1 cells while higher concentrations （1 μmol/L and 5 μmol/L） had strong anti-tumor effect with the inhibiting rates of 40.07±7.98% and 88.67±2.88%, respectively. Annexin V-FITC/PI flow cytometry showed that the apoptotic rates of CEM-C1 ceils were significantly increased after 48 hours treatment of different concentrations of ATO. RT-PCR demonstrated up-regulated mRNA expression of pro-apoptotic protein Bad and PDCD4 but down-regulated mRNA expression of anti-apoptotic protein XIAP when CEM-C1 cells were treated with different concentrations of ATO at different time points. The MCL-1 mRNA expression was down-regulated only after the treatment of 5 μmol/L ATO. Conclusion： ATO can inhibit cell proliferation and induce cell apoptosis in GC-resistant CEM-C1 cells. The molecular mechanisms might involve the increased mRNA expression of pro-apoptotic protein Bad and PDCD-4, and rapid down-regulation of XIAP mRNA expression.

Cytogenetic Characteristics of Childhood Acute Lymphoblastic Leukemia:A Study of 1541 Chinese Patients Newly Diagnosed between 2001 and 2014

Objective:Cytogenetic abnormalities have been proven to be the most valuable parameter for risk stratification of childhood acute lymphoblastic leukemia(ALL).However,studies on the prevalence of cytogenetic abnormalities and their correlation to clinical features in Chinese pediatric patients are limited,especially large-scale studies.Methods:We collected the cytogenetics and clinical data of 1541 children newly diagnosed with ALL between 2001 and 2014 in four Chinese hospitals,and retrospectively analyzed their clinical features,prognosis and risk factors associated with pediatric ALL.

Dehydroabietic acid chemosensitizes drug-resistant acute lymphoblastic leukemia cells by downregulating survivin expression

Objective:To explore the mechanism of drug resistance in acute lymphoblastic leukemia and the anti-tumor effect of combination therapy of dehydroabietic acid and vincristine against acute lymphoblastic leukemia cells.Methods:Acute lymphoblastic leukemia cells REH and CCRFCEM were employed to detect the anti-tumor effect of vincristine and doxorubicin on proliferation and apoptosis using EdU assay,human active caspase-3 Quantikine ELISA kit,and flow cytometry.Vincristine-resistant REH cells(REH-R),survivin knockdown and overexpressing REH cells were established to verify the role of survivin in drug resistance.Additionally,in vitro and in vivo assays were performed to determine the effect of dehydroabietic acid on the cytotoxicity of vincristine.Results:Vincristine and doxorubicin markedly suppressed proliferation and induced apoptosis of REH and CCRF-CEM cells.Survivin expression was upregulated in REH-R cells compared with REH cells.Knockdown of survivin expression obviously restored the sensitivity of REH-R cells to vincristine.Akt phosphorylation was also increased in REH-R cells compared to REH cells.In addition,LY294002,a PI3k/Akt pathway blocker,inhibited survivin expression and enhanced cytotoxicity of vincristine to REH-R cells.Dehydroabietic acid effectively reduced survivin expression in REH-R cells,thereby enhancing the therapeutic effect of vincristine on drug-resistant cells.Survivin overexpression markedly reduced the effect of dehydroabietic acid on enhancing the anti-proliferation and inducing apoptosis effect of vincristine.Moreover,the combination of dehydroabietic acid with vincristine significantly extended the survival rate in a mouse xenograft model of acute lymphoblastic leukemia,compared with vincristine treatment alone.Conclusions:Dehydroabietic acid may be used as a potential candidate for the treatment of acute lymphoblastic leukemia in combination with vincristine.