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Acute Lymphocytic Leukemia (ALL)

Acute lymphoblastic leukemia (also known as acute lymphocytic leukemia or ALL) is a disease where too many immature lymphocytes (a type of white blood cell) are found in the blood and bone marrow. Symptoms can include persistent fever, weakness or tiredness, achiness in the bones or joints, or swollen lymph nodes. Adult ALL and its treatment is usually different to childhood ALL. Almost a third of adult patients have a specific chromosome translocation; "Philadelphia Positive" ALL.

(UK spelling: Leukaemia)

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Information for Patients and the Public
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Latest Research Publications
Childhood ALL
Molecular Genetics of ALL

Information Patients and the Public (10 links)

Information for Health Professionals / Researchers (7 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Zhang R, Chen J, Zheng H, et al.
Effects of medium chain triglycerides on body fat distribution and adipocytokine levels in children with acute lymphoblastic leukemia under chemotherapy.
Medicine (Baltimore). 2019; 98(33):e16811 [PubMed] Related Publications
Glucocorticoids used to treat acute lymphoblastic leukemia (ALL) are associated with cytotoxicity and obesity. The aim of the study was to investigate the effects of high-proportion medium chain triglyceride (MCT) on body fat distribution and levels of leptin and adiponectin during chemotherapy of children with ALL.New-onset ALL children treated at the Guangzhou Women and Children's Medical Center between March 2016 and March 2017 were enrolled. Children were divided into the MCT and control groups. For the MCT group, high-proportion MCT nutrition preparation was added to the diet, while no MCT was added for the control group. The MCT group was further divided into subgroups A and B based on the amount of supplement. Waist circumference, hip circumference, waist-to-hip ratio, bone marrow concentrations of leptin and adiponectin, and leptin-to-adiponectin ratio were measured before and on days 19 and 46 of chemotherapy. Body weight and body mass index (BMI) were measured on admission and discharge.Waist circumference in the control group increased by day 46 (P = .047), but did not change in the MCT group. The BMI of the children in the control group was higher than those in the MCT group on admission (P = .003), but not different at discharge. No significant differences in hip circumference, leptin levels, adiponectin levels, and body weight were observed between the 2 groups.This preliminary study suggests that short-term supplementation of high-proportion MCT nutrition preparation may help reduce the centripetal distribution of adipose induced by the application of glucocorticoids in children with ALL. This will have to be confirmed in future studies.

Zhang C, Ma YY, Liu J, et al.
Preventive infusion of donor-derived CAR-T cells after haploidentical transplantation: Two cases report.
Medicine (Baltimore). 2019; 98(29):e16498 [PubMed] Related Publications
RATIONALE: Relapse is the main cause of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Unfortunately, there are no efficient methods to prevent relapse after allo-HSCT. Chimeric antigen receptor T (CAR-T) cells have achieved favorable outcomes in the treatment of refractory/relapsed acute lymphoblastic leukemia (ALL) because of their strong anti-leukemia activity. However, it is unclear whether the CAR-T cells constructed using viral systems can be used as preventive infusions to prevent relapse after haploidentical HSCT.
PATIENT CONCERNS: Two patients with ALL with high risk received haploidentical HSCT.
DIAGNOSES: Two patients were diagnosed with ALL with high risk.
INTERVENTIONS: Patients received preventive infusion of donor-derived CAR-T cells constructed using viral systems on day 60 after haploidentical HSCT.
OUTCOMES: The CAR-T cells were continually detected, and no graft versus host disease developed. The two patients survived with disease-free for 1 year and 6 months, respectively.
LESSONS: Preventive infusion of donor-derived CAR-T cells after haploidentical HSCT may be safe and that immunosuppressors may not affect the proliferation of CAR-T cells.

Chunxia D, Meifang W, Jianhua Z, et al.
Tobacco smoke exposure and the risk of childhood acute lymphoblastic leukemia and acute myeloid leukemia: A meta-analysis.
Medicine (Baltimore). 2019; 98(28):e16454 [PubMed] Free Access to Full Article Related Publications
OBJECTIVE: Tobacco smoke contains carcinogens known to damage somatic and germ cells. In this study, we investigated the effect of tobacco smoking on the risk of childhood acute lymphoblastic leukemia (ALL) and myeloid leukemia (AML).
METHODS: Information about tobacco smoking exposures of the mother before, during, and after pregnancy was collected via PubMed, Embase, and Web of Science databases through November 5, 2018. We performed to evaluate the association between smoking exposure and the risk of childhood ALL and AML. Study selection, data abstraction, and quality assessment were performed by 2 independent reviewers. Random effects models were used to obtain summary odds ratios (ORs) and 95% confidence intervals (CIs).
RESULTS: Nineteen case-control studies of childhood leukemia (age < 15 years) conducted in 9 countries from 1974 to 2018. Maternal smoking exposures did not a significant association with childhood ALL (OR = 1.004, 95% CI 0.953-1.058, P = .881) and AML (OR = 0.92, 95% CI 0.815-1.038, P = .177) during exposure time windows. However, there was an association with paternal smoking and ALL (OR = 1.15, 95% CI 1.038-1.275, P = .007). Paternal smoking in AML showed there was no association with smoking exposures and childhood AML (OR = 1.133, 95% CI 0.943-1.362, P = .181). Next, maternal daily cigarettes consumption showed no associations with ALL (OR = 1.08, 95% CI 1.000-1.168, P = .051) during pregnancy. No association with maternal daily smoking and AML (OR = 0.909, 95% CI 0.682-1.211, P = .514). Paternal daily cigarettes consumption was associated with increased risks of childhood ALL (OR = 1.200, 95% CI 1.112-1.302, P = .000). The higher consumption of paternal smoking (more than 10 per day) was significantly related to childhood ALL. Paternal daily smoking consumption also was related to AML (OR = 1.242, 95% CI 1.031-1.496, P = .022).
CONCLUSION: Maternal smoking before, during, or after pregnancy was not associated with childhood ALL or AML. However, paternal smoking was related to a significantly elevated risk of childhood ALL during pregnancy, but not for AML. Maternal daily smoking consumption was not associated with ALL or AML during pregnancy. The higher consumption of paternal smoking were, the higher the risk of childhood ALL or AML.

Sekiguchi Y, Wakabayashi M, Takizawa H, et al.
A Case of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia with Aspergillus Brain Abscess and Invasive Pulmonary Aspergillosis Successfully Treated with Voriconazole Followed by Cord Blood Transplantation.
Gan To Kagaku Ryoho. 2019; 46(7):1203-1209 [PubMed] Related Publications
A 59-year-old female was diagnosed as pulmonary aspergillosis(IPA)while remission induction therapy for Philadelphia chromosome-positive acute lymphoblastic leukemia. Liposomal amphotericin B improved the fungal serodiagnostic markers, however,the IPA worsened. She also developed an Aspergillus brain abscess,which, while being undetectable on CT,was detected as multiple nodular lesions by MRI. A definitive diagnosis was made by polymerase chain reaction(PCR)of brain biopsy specimens. Voriconazole(VRCZ)was effective,and cord blood transplantation was performed. She has received VRCZ for a long time. There are no relapse of either the IPA or the Aspergillus brain abscess.

Wińska P, Widło Ł, Skierka K, et al.
Simultaneous Inhibition of Protein Kinase CK2 and Dihydrofolate Reductase Results in Synergistic Effect on Acute Lymphoblastic Leukemia Cells.
Anticancer Res. 2019; 39(7):3531-3542 [PubMed] Related Publications
BACKGROUND/AIM: Recently, we demonstrated the ability of inhibitors of protein kinase 2 (casein kinase II; CK2) to enhance the efficacy of 5-fluorouracil, a thymidylate synthase (TYMS)-directed drug for anticancer treatment. The present study aimed to investigate the antileukemic effect of simultaneous inhibition of dihydrofolate reductase (DHFR), another enzyme involved in the thymidylate biosynthesis cycle, and CK2 in CCRF-CEM acute lymphoblastic leukemia cells.
MATERIALS AND METHODS: The influence of combined treatment on apoptosis and cell-cycle progression, as well as the endocellular level of DHFR protein and inhibition of CK2 were determined using flow cytometry and western blot analysis, respectively. Real-time quantitative polymerase chain reaction was used to examine the influence of silmitasertib (CX-4945), a selective inhibitor of CK2 on the expression of DHFR and TYMS genes.
RESULTS: The synergistic effect was correlated with the increase of annexin V-binding cell fraction, caspase 3/7 activation and a significant reduce in the activity of CK2. An increase of DHFR protein level was observed in CCRF-CEM cells after CX-4945 treatment, with the mRNA level remaining relatively constant.
CONCLUSION: The obtained results demonstrate a possibility to improve methotrexate-based anti-leukemia therapy by simultaneous inhibition of CK2. The effect of CK2 inhibition on DHFR expression suggests the important regulatory role of CK2-mediated phosphorylation of DHFR inside cells.

Metzinger MN, Verghese C, Hamouda DM, et al.
Chimeric Antigen Receptor T-Cell Therapy: Reach to Solid Tumor Experience.
Oncology. 2019; 97(2):59-74 [PubMed] Related Publications
Chimeric antigen receptor (CAR) modified T-cell therapy, a unique platform technology highlighting precision medicine through utilization of molecular biology and cell-based therapeutics has shown unprecedented rates in patients with hematological malignancies such as acute lymphocyte leukemia, non-Hodgkin's lymphoma and multiple myeloma (MM). With the approval of CD19-targeted CAR T-cells by the Food and Drug Administration in acute lymphoblastic leukemia (ALL) and NHL, this technology is positioned for aggressive expansion to combination therapeutic opportunities and proof of principle towards utility in other malignant disorders. However, despite the impressive results seen with hematological malignancies, CAR T-cells have shown limited efficacy in solid tumors with several unsuccessful preclinical studies. Regardless, these attempts have provided us with a better understanding of the imminent challenges specific to solid tumors even if they have not so far led to expanded clinical treatment opportunities outside ALL/NHL/MM. This review summarizes our current understanding of CAR T-cell mechanism of action, while presenting the major limitations of CAR T-cell derived treatments in solid tumors. We further discuss recent findings and present new potential strategies to overcome the challenges facing solid tumor targeting by CAR T-cell platforms.

Tian L, Shao Y, Nance S, et al.
Long-read sequencing unveils IGH-DUX4 translocation into the silenced IGH allele in B-cell acute lymphoblastic leukemia.
Nat Commun. 2019; 10(1):2789 [PubMed] Free Access to Full Article Related Publications
IGH@ proto-oncogene translocation is a common oncogenic event in lymphoid lineage cancers such as B-ALL, lymphoma and multiple myeloma. Here, to investigate the interplay between IGH@ proto-oncogene translocation and IGH allelic exclusion, we perform long-read whole-genome and transcriptome sequencing along with epigenetic and 3D genome profiling of Nalm6, an IGH-DUX4 positive B-ALL cell line. We detect significant allelic imbalance on the wild-type over the IGH-DUX4 haplotype in expression and epigenetic data, showing IGH-DUX4 translocation occurs on the silenced IGH allele. In vitro, this reduces the oncogenic stress of DUX4 high-level expression. Moreover, patient samples of IGH-DUX4 B-ALL have similar expression profile and IGH breakpoints as Nalm6, suggesting a common mechanism to allow optimal dosage of non-toxic DUX4 expression.

Zang YN, Wang SZ, Qin Y, et al.
Population pharmacokinetic study of delayed methotrexate excretion in children with acute lymphoblastic leukemia
Int J Clin Pharmacol Ther. 2019; 57(8):402-407 [PubMed] Related Publications
OBJECTIVE: To investigate the population pharmacokinetics of delayed methotrexate (MTX) excretion in children with acute lymphoblastic leukemia (ALL).
MATERIALS AND METHODS: A total of 1,659 plasma concentration samples of MTX from 190 patients with 1 - 4 courses (plasma concentrations > 0.1 µmol/L) were collected in this study. The data analysis was performed using Phoenix NLME 1.3 software. The covariates included age, body surface area (BSA), body weight, alkaline phosphatase (ALP), aspartate aminotransferase (AST), alanine transaminase (ALT), total bilirubin (TBIL), and serum creatinine (SCr). The final model was validated by bootstrap resampling procedures (1,000 runs) and visual predictive check (VPC) method.
RESULTS: The data were best described by a two-compartment linear pharmacokinetic model. The mean values of clearance (CL) and distribution volume (V
CONCLUSION: The final model was demonstrated as appropriate and effective for assessing the pharmacokinetic parameters of delayed MTX excretion in children with ALL.

Rahimi Babasheikhali S, Rahgozar S, Mohammadi M
Ginger extract has anti-leukemia and anti-drug resistant effects on malignant cells.
J Cancer Res Clin Oncol. 2019; 145(8):1987-1998 [PubMed] Related Publications
PURPOSE: Based on the poor prognosis of drug resistance in pediatric acute lymphoblastic leukemia (ALL) and adverse effects of chemotherapy, this study was aimed to evaluate the effect of several herbal extracts on leukemic cells.
METHODS: Two subtypes of T- and B-ALL cell lines, followed by ALL primary cells were treated with cinnamon, ginger, and green tea extracts, alone or in combination with methotrexate (MTX). Possible apoptosis was investigated using Annexin-V/PI double staining. Real-time PCR was applied to evaluate the expression levels of related ABC transporters upon combination therapy.
CONCLUSION: To the best of our knowledge, this is the first study that reveals the antileukemic effect of ginger extract on both, pediatric ALL cell lines and primary cells.

Li F, Wang J, Liu A, et al.
Prolonged lumbosacral pain as the initial presentation in acute lymphoblastic leukemia in an adult: A case report.
Medicine (Baltimore). 2019; 98(24):e15912 [PubMed] Free Access to Full Article Related Publications
RATIONALE: The differential diagnosis of conditions manifesting as bone and joint pain is complex. Although many individuals with acute leukemia experience bone pain, lumbosacral pain as an early feature of acute lymphoblastic leukemia (ALL) is rare.
PATIENT CONCERNS: Here we report a case of an adult who presented with a 7-month history of persistent lumbosacral pain which had become more severe during the previous month.
DIAGNOSES: Prior to referral, his full blood count revealed no abnormalities, and a computerized tomography scan revealed mild bone hyperplasia of his lumbar vertebrae, with disc herniations of L3-S1. His blood biochemistry and urinary test results had been normal. After referral to our clinic, tests of the morphology, immunology, cytogenetics, and molecular biology of his bone marrow led to a diagnosis of MLL-AF4 fusion positive B-cell ALL.
INTERVENTIONS: Prior to his referral, he had been treated with painkillers by local doctors. The painkillers initially provided pain relief, but their effect wore off over time. After diagnosis, he was started on an adult ALL chemotherapy protocol.
OUTCOMES: His symptoms resolved within a week of starting chemotherapy. At his most recent assessment, 10 months after diagnosis, he was on maintenance chemotherapy and in remission.
LESSONS: This case illustrates that prolonged lumbosacral pain may be a symptom of a life-threatening condition, rather than only attributable to chronic inflammation or disk herniations. Therefore, clinicians need to pay attention to subtle differences in the clinical presentation of patients with lumbosacral pain.

Militaru A, Zus S, Cimpean AM, et al.
Early Diagnosis of Cardiotoxicity in Patients Undergoing Chemotherapy for Acute Lymphoblastic Leukemia.
Anticancer Res. 2019; 39(6):3255-3264 [PubMed] Related Publications
BACKGROUND/AIM: Chemotherapy-induced cardiotoxicity may be observed during treatment or may cause severe cardiac failure as the main cause of death, even several years after therapy implementation. Herein, the aim was to establish the early diagnosis of cardiotoxicity through the periodic evaluation of the left ventricular (LV) and vascular remodeling parameters, in patients with acute lymphoblastic leukemia (ALL).
MATERIALS AND METHODS: The study population included 35 patients diagnosed with ALL, evaluated before and 3 months after starting chemotherapy, measuring systolic and diastolic parameters of the LV and intima-media thickness (IMT), arterial stiffness aortic pulse wave velocity (PWVAo) and ankle-brachial index (ABI).
RESULTS: After the first 2 cycles of chemotherapy, all patients experienced a drop in LV ejection fraction (LVEF) (p<0.001), and 12 patients suffered a decrease of LVEF<50%. The ABI (p<0.05) and the global longitudinal strain (GLS) (p<0.001) decreased, while IMT and PWVAo (p<0.001) increased, proving a subclinical deterioration of the LV function and vascular remodeling.
CONCLUSION: Assessment of cardiovascular risk factors before chemotherapy initiation in ALL patients may be helpful for an early diagnosis of chemotherapy-induced cardiotoxicity, thus contributing to early treatment and a subsequent decrease of death caused by such cardiovascular complications.

Wang Y, Zhang X, Dong L, et al.
Acute lymphoblastic leukemia with pancreas involvement in an adult patient mimicking pancreatic tumor: A case report.
Medicine (Baltimore). 2019; 98(23):e15685 [PubMed] Free Access to Full Article Related Publications
RATIONALE: Acute lymphoblastic leukemia (ALL) is a malignant disease originating from abnormal proliferation of B or T lymphocytes in bone marrow (BM). Invasion of the pancreas is extremely rare in adults.
PATIENT CONCERNS: In this article, we report a case presenting that ALL invades the pancreas, as well as liver, kidney, and duodenum detected by magnetic resonance image. The patient was misdiagnosed as pancreatic tumor at initial since hemogram was unremarkable.
DIAGNOSES: The diagnosis of ALL was established based on the endoscopic ultrasonography-guided fine-needle aspiration and bone marrow examination, showing BCR/ABL gene positive.
INTERVENTIONS: The patient was actively treated with chemotherapy. Hematological remission was obtained and the lesions in the pancreas disappeared.
OUTCOMES: The patient finally died of complication from fungal pneumonia and central nervous system involvement 12 months after diagnosis.
LESSONS: Under the context of infection, persistent or intermittent fever and complete blood count are not significant prognoses of pancreatic involvement for adult with ALL. We hope that this case will help hepatobiliary and pancreatic surgeon to be aware of this kind of disease as pancreatic carcinoma and pancreas involvement by ALL have totally different treatment strategy.

Grunnan JD, Rosthøj S
Time course of peripheral blood count recovery during induction chemotherapy for childhood acute lymphoblastic leukemia.
Hematology. 2019; 24(1):467-472 [PubMed] Related Publications

Piroozian F, Bagheri Varkiyani H, Koolivand M, et al.
The impact of variations in transcription of DICER and AGO2 on exacerbation of childhood B-cell lineage acute lymphoblastic leukaemia.
Int J Exp Pathol. 2019; 100(3):184-191 [PubMed] Article available free on PMC after 01/06/2020 Related Publications
The expression of microRNA in eukaryotic cells is subject to tightly regulated processing. The altered expression of microRNAs in a number of cancers suggests their contribution to disease pathogenesis, where processing pathways may be involved in disease pathogenesis. In the present study, we evaluated changes in the profile of two main components of microRNA biogenesis, AGO2 and DICER, and assessed their correlation with disease progression in childhood acute lymphoblastic leukaemia (ALL). To achieve this aim, 25 patients afflicted with ALL were included in the study along with 25 healthy subjects as control. The expression level of AGO2 and DICER was evaluated by real-time PCR. The results revealed an increase in the expression of DICER and a decrease in AGO2 in patients. The correlation between the alteration levels of these genes with pathologic events was also studied. This increase or decrease proved to be directly correlated with the progression of the disease particularly in L1 to L2. According to the obtained results, it can be deduced that dysregulation in transcription of DICER and AGO2, involved in the formation of mature microRNAs in cytoplasm of ALL cancer cells, is a part of the pathological molecular mechanism implicated in the exacerbation of this malignancy. Therefore, the genes involved in microRNAs biogenesis that have been studied here could be considered as candidate prognostic markers especially in childhood ALL which will help towards a better understanding of the molecular basis of ALL.

Conant JL, Czuchlewski DR
BCR-ABL1-like B-lymphoblastic leukemia/lymphoma: Review of the entity and detection methodologies.
Int J Lab Hematol. 2019; 41 Suppl 1:126-130 [PubMed] Related Publications
BCR-ABL1-like B-lymphoblastic leukemia/lymphoma (BCR-ABL1-like ALL or Ph-like ALL) is a neoplastic proliferation of lymphoblasts that has a gene expression profile similar to that of B-ALL with t(9;22)(q34.1;q11.2) BCR-ABL1, but lacks that gene fusion. It is associated with poor prognosis and is seen in 10%-20% of pediatric cases and 20%-30% of adult cases of ALL. It is included as a provisional entity in the revised 4th edition of the WHO Classification. A variety of different genetic abnormalities are identified in this entity, but they all converge on pathways that are potentially responsive to the addition of targeted therapy to conventional chemotherapy. Thus, it is important to screen for BCR-ABL1-like ALL, particularly in adults and pediatric patients with high-risk clinical features. Here, we provide a brief overview of the genetic profile and clinical features of BCR-ABL1-like ALL and review laboratory methodologies for routine identification of this genetically heterogeneous entity.

Jiang H, Liu L, Guo T, et al.
Improving the safety of CAR-T cell therapy by controlling CRS-related coagulopathy.
Ann Hematol. 2019; 98(7):1721-1732 [PubMed] Related Publications
The CD19-targeted chimeric antigen receptor T cell (CAR-T) therapy has been widely proved effective on relapsed and refractory (r/r) B cell acute lymphoblastic leukemia (B-ALL). Meanwhile, CAR-T therapy-related toxicities, including cytokine release syndrome (CRS) and neurological toxicities, are drawing researchers' attention. In addition, our research team notices that coagulopathy and even disseminated intravascular coagulation (DIC) are common problems during CAR-T therapy. In our phase 1/2 clinical trial (NCT02965092), 53 r/r B-ALL patients underwent leukapheresis on day - 11 and received lymphodepleting chemotherapy on day - 7 to day - 5. Finally, they received split infusions of anti-CD19 CAR-T cells on day 0 to day 2. Plasma concentrations of tissue factor (TF) and platelet endothelial cell adhesion molecular-1 (PECAM-1) were also measured to identify the mechanism of coagulation disorders. The overall 1-month remission rate of the 53 patients was 88.7%. During the treatment course, 19 patients experienced grade 3-4 CRS, 8 patients developed grade 2-3 neurological toxicities. Beyond that, 30 patients (30/53, 56.6%) suffered from coagulation disorders, and half of them should be diagnosed as DIC. Benefiting from replacement and anticoagulant therapy, 14 patients successfully got out of the conditions of DIC. Remarkably, the severity of coagulopathy was positively correlated with CRS grade. What is more, plasma TF and PECAM-1 levels indicated that vascular endothelial factors played key roles in the process of CRS-related coagulopathy. To conclude, coagulation disorders frequently happen during CAR-T therapy. TF and PECAM-1 are of great importance in the etiology and pathogenesis of coagulation problems. Early and proper interventions targeted at CRS-related coagulopathy contribute a lot to the control of side effects in CAR-T therapy.

Xu X, Huang L, Zhang Z, et al.
Targeting non-oncogene ROS pathway by alantolactone in B cell acute lymphoblastic leukemia cells.
Life Sci. 2019; 227:153-165 [PubMed] Related Publications
AIMS: Alantolactone (ALT) is active component of natural product Inula helenium with a lot of pharmacological effects, including anti-tumor effect. The present work aimed to explore the antitumor effect of ALT in B cell acute lymphoblastic leukemia (B-ALL).
MAIN METHODS: B-ALL cells were treated with various concentrations of ALT, and then trypan blue assay, Annexin V/PI staining assay, PI staining assay, western blot analysis were employed to measure the effect of ALT on viability, apoptosis and cell cycle in B-ALL cells. In addition, a synthetic bioinformatics method was used to predict the underlying mechanism of antitumor effect of ALT. Then Reactive Oxygen Species (ROS) probe Dihydroethidium (DHE) and 2',7'-Dichlorodihydrofluorescein diacetate (DCFH-DA) were used to detect accumulation of cellular ROS. Meanwhile, DNA damage was identified by 8-oxoG, p-ATM1987, γ-H2AX and comet assay. In addition, activity of glutathione reductase (GR), thioredoxin reductase (TrxR) and catalase were measured and overexpressed in SEM and RS4;11 cells to study the inhibition on these enzymes. Finally, B-ALL NOD-SCID mouse model was used to test its performance in vivo.
KEY FINDINGS: ALT showed good antitumor effect in B-ALL in vivo and in vitro through inducing ROS overload, which led to DNA damage. In addition, we found ROS overload caused by ALT was due to its direct inhibition on reductase.
SIGNIFICANCE: We found that ALT, a natural product, showing a promising tactic in the therapy of B-ALL by targeting ROS pathway.

Bai J, Li L, Li Y, et al.
Methylation of the promoter region of the MTRR gene in childhood acute lymphoblastic leukemia.
Oncol Rep. 2019; 41(6):3488-3498 [PubMed] Related Publications
Epigenetic analysis of the association between the methylation status of the promoter region of the MTRR (5‑methyltetrahydrofolate‑homocysteine methyltransferase reductase) gene and the risk of acute lymphoblastic leukemia (ALL) in children plays an important role in the early diagnosis, assessment of the malignant degree, treatment and evaluation of the risk of relapse and prognosis of the disease. In the present study, RT‑qPCR was used to detect the mRNA levels of the MTRR and MTHFR (methylenetetrahydrofolate reductase) genes in the bone marrow of 20 ALL patients and 20 age‑ and sex‑matched controls with normal bone marrow. The methylation pattern of the MTRR promoter region in eligible DNA samples was quantitatively analyzed using MALDI‑TOF MS. The results indicated that the mRNA expression level of MTRR in the bone marrow from children with ALL was lower than that in the control samples (P<0.05), but no significant difference was detected in the MTHFR gene between the two groups (P>0.05). According to the risk classification of ALL in children with high, medium and low risk, the low‑risk group had a higher methylation rate of CpG_6 compared to the medium‑risk group. However, the medium‑risk group had a higher CpG_46.47 methylation rate compared to the low‑risk group. The methylation rates of CpG_26 and CpG_46.47 in the high‑risk group were higher than these rates in the low‑risk group, while the CpG_42.23.44 methylation rate was lower in the high‑risk group than in the low‑risk group (P<0.05). The methylation rates at CpG_1, CpG_10, CpG_48 sites, score and the average methylation rate in the ALL‑H (high) group (≥50x109/l) were lower than these in the ALL‑NH (not high) group (<50x109/l) and the control group (P<0.05). We conclude that abnormal MTRR mRNA expression and the methylation of the MTRR promoter can be used to classify the risk of ALL in children.

Hrabovský Š, Folber F, Doubek M
Therapy of Relapsed/Refractory Acute Lymphoblastic Leukemia Today and Tomorrow.
Klin Onkol. 2019; 32(2):90-96 [PubMed] Related Publications
BACKGROUND: New diagnostics and treatments, including the use of new drugs, have advanced considerably the treatment of acute lymphoplastic leukemia (ALL) in the past few years. Monoclonal antibodies and immunoconjugates targeting antigens CD19 and CD22 show greater efficacy and more favourable toxicity profiles than standard salvage chemotherapeutic protocols. Two of these drugs - blinatumomab and inotuzumab ozogamicin - have already made their way into clinical practice. Ponatinib and other new generation tyrosine kinase inhibitors allow dose reduction of intensive cytostatic regimens in Ph-positive ALL patients and slowly start to overshadow the importance of allogeneic hematopoietic cell transplants. For the time being, their use is reserved for relapsed/refractory ALL, but they are already available as a first line therapy in clinical trials. An entirely new group of living drugs is emerging for the treatment of ALL - chimeric antigen receptor T-cells produced by genetic modification of native human cells. Chimeric antigen receptor T-cells can be looked upon as in vitro trained professional blast killers. They show an efficacy never seen before for the treatment of relapsed/refractory ALL. On the other hand, this treatment still presents significant risks, mainly due to cytokine release syndrome. Ruxolitinib, mTOR inhibitors, bortezomib, and other drugs for targeted treatment of ALL are currently being evaluated in clinical trials.
PURPOSE: The article focuses on current options and news in the field of relapsed and refractory ALL treatment. This work was created at Masaryk University as part of the project “New Approaches in Research, Diagnostics and Therapy of Hematological Malignancies VI”, number MUNI/A/1105/2018, supported by Czech Ministry of Education, Youth and Sports in 2019.  The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 28. 8. 2018 Accepted: 10. 1. 2019.

Park H, Youk J, Shin DY, et al.
Micafungin prophylaxis for acute leukemia patients undergoing induction chemotherapy.
BMC Cancer. 2019; 19(1):358 [PubMed] Article available free on PMC after 01/06/2020 Related Publications
BACKGROUND: Micafungin is a well-tolerated and effective prophylactic antifungal agent used in hematologic diseases. In this prospective trial, we evaluated the efficacy and safety of prophylactic micafungin during first induction chemotherapy in patients with acute leukemia. We also compared outcomes of prophylactic micafungin with those of prophylactic posaconazole in acute myeloid leukemia (AML).
METHODS: Medically fit patients with newly diagnosed acute leukemia received 50 mg micafungin intravenously once daily from the initiation of first induction chemotherapy to recovery of neutrophil count, suspected fungal infection, or unacceptable drug-related toxicity ( Clinicaltrials.gov number, NCT02440178). The primary end point was incidence of invasive fungal infection, and the secondary end points were adverse events of prophylactic micafungin and mortality during induction therapy.
RESULTS: The 65 patients (median age = 51 years, male:female = 34:31) enrolled in this study had diagnoses of AML (33, 50.8%), acute lymphoblastic leukemia (31, 47.7%), and acute biphenotypic leukemia (1, 1.5%). Median duration of micafungin treatment was 24 days (range 1-68), with proven invasive fungal disease in one patient (1.5%) and possible fungal infection in two patients (3.1%). Three of the patients (4.6%) experienced the following adverse events, but all events were tolerable: liver function abnormality (Grade 2, n = 1; Grade 3, n = 1) and allergic reaction (Grade 2, n = 1). Three patients died during induction therapy, and invasive aspergillosis pneumonia was the cause of death for one of those patients. Overall, 19 patients (29.2%) discontinued prophylactic micafungin, and 18 (27.7%) patients switched to another antifungal agent. We observed no fungal infections caused by amphotericin B-resistant organisms. In AML patients, outcomes of prophylactic micafungin during induction chemotherapy did not differ significantly with those of prophylactic posaconazole with regard to incidence of fungal infections, rate of discontinuation, or safety.
CONCLUSIONS: Our study demonstrates that prophylactic micafungin is safe and effective in patients with acute leukemia undergoing induction chemotherapy. Outcomes in patients with AML were similar to those of prophylactic posaconazole, indicating the usefulness of micafungin as a prophylactic antifungal agent during induction chemotherapy for AML.
TRIAL REGISTRATION: Clinicaltrials.gov NCT02440178, registered May 12th 2015.

Ding C, Huang Y, Shi M, et al.
CD20-negative primary middle ear diffuse large B-cell lymphoma coexpressing MYC and BCL-2 secondary to acute lymphoblastic leukemia: A case report.
Medicine (Baltimore). 2019; 98(15):e15204 [PubMed] Article available free on PMC after 01/06/2020 Related Publications
RATIONALE: Second diffuse large B-cell lymphoma (DLBCL) after treatment of acute lymphoblastic leukemia (ALL) is uncommon. To our knowledge, primary middle ear DLBCL which presents CD20-negative and coexpression of MYC and BCL-2 has not been reported yet.
PATIENT CONCERNS: A 20-year-old Chinese man complained fever and weakness for 2 months. Subsequently bone marrow morphology and flow cytometry immunophenotype suggested ALL. Administrated with 9 cycles of multiagent combined chemotherapy, he felt right ear progressive hearing loss, otalgia, aural fullness. Otoendoscopic examination revealed a pitchy mass obstructing the right external auditory canal. Then the mass resection was performed for biopsy and immunohistochemistry examination.
DIAGNOSIS: The mass was diagnosed as DLBCL which was negative for CD20 and double expression of MYC and BCL-2.
INTERVENTIONS: Chemotherapy.
OUTCOMES: The patient eventually gave up and died of severe infection.
LESSONS: Although intensive chemotherapy has markedly improved the survival of ALL, more and more secondary cancers have been reported. In addition, primary middle ear lymphoma is much rare; hence, it is easy to be misdiagnosed. Furthermore, DLBCL with negative CD20 and double expression of MYC and BCL-2 is aggressive, which is characterized by chemotherapy resistance and inferior survival rates. We discuss this case aiming at raising awareness of tumors secondary to ALL and exploring the appropriate treatment options for the rare DLBCL.

Ayón-Pérez MF, Pimentel-Gutiérrez HJ, Durán-Avelar MJ, et al.
IKZF1 Gene Deletion in Pediatric Patients Diagnosed with Acute Lymphoblastic Leukemia in Mexico.
Cytogenet Genome Res. 2019; 158(1):10-16 [PubMed] Related Publications
The IKZF1 gene is formed by 8 exons and encodes IKAROS, a transcription factor that regulates the expression of genes that control cell cycle progression and cell survival. In general, 15-20% of the patients with preB acute lymphoblastic leukemia (preB ALL) harbor IKZF1 deletions, and the frequency of these deletions increases in BCR-ABL1 or Ph-like subgroups. These deletions have been associated with poor treatment response and the risk of relapse. The aim of this descriptive study was to determine the frequency of IKZF1 deletions and the success of an induction therapy response in Mexican pediatric patients diagnosed with preB ALL in 2 hospitals from 2017 to August 2018. Thirty-six bone marrow samples from patients at the Instituto Nacional de Pediatría in Mexico City and the Centro Estatal de Cancerología in Tepic were analyzed. The IKZF1 deletion was identified by MLPA using the SALSA MLPA P335 ALL-IKZF1 probemix. Deletions of at least 1 IKZF1 exon were observed in 7/34 samples (20.6%): 3 with 1 exon deleted; 1 with 2 exons, 1 with 5 exons, 1 with 6 exons, and 1 patient with a complete IKZF1 deletion. This study was descriptive in nature; we calculated the frequency of the IKZF1 gene deletion in a Mexican pediatric population with preB ALL as 20.6%.

Sharma ND, Nickl CK, Kang H, et al.
Epigenetic silencing of SOCS5 potentiates JAK-STAT signaling and progression of T-cell acute lymphoblastic leukemia.
Cancer Sci. 2019; 110(6):1931-1946 [PubMed] Article available free on PMC after 01/06/2020 Related Publications
Activating mutations in cytokine receptors and transcriptional regulators govern aberrant signal transduction in T-cell lineage acute lymphoblastic leukemia (T-ALL). However, the roles played by suppressors of cytokine signaling remain incompletely understood. We examined the regulatory roles of suppressor of cytokine signaling 5 (SOCS5) in T-ALL cellular signaling networks and leukemia progression. We found that SOCS5 was differentially expressed in primary T-ALL and its expression levels were lowered in HOXA-deregulated leukemia harboring KMT2A gene rearrangements. Here, we report that SOCS5 expression is epigenetically regulated by DNA methyltransferase-3A-mediated DNA methylation and methyl CpG binding protein-2-mediated histone deacetylation. We show that SOCS5 negatively regulates T-ALL cell growth and cell cycle progression but has no effect on apoptotic cell death. Mechanistically, SOCS5 silencing induces activation of JAK-STAT signaling, and negatively regulates interleukin-7 and interleukin-4 receptors. Using a human T-ALL murine xenograft model, we show that genetic inactivation of SOCS5 accelerates leukemia engraftment and progression, and leukemia burden. We postulate that SOCS5 is epigenetically deregulated in T-ALL and serves as an important regulator of T-ALL cell proliferation and leukemic progression. Our results link aberrant downregulation of SOCS5 expression to the enhanced activation of the JAK-STAT and cytokine receptor-signaling cascade in T-ALL.

Paul S, Rausch CR, Nasnas PE, et al.
Treatment of relapsed/refractory acute lymphoblastic leukemia.
Clin Adv Hematol Oncol. 2019; 17(3):166-175 [PubMed] Related Publications
Patients with relapsed or refractory acute lymphoblastic leukemia (R/R ALL) have dismal outcomes, with survival of less than 6 months, and treatment options in the salvage setting have been limited to conventional cytotoxic chemotherapy with minimal activity. Advances in the development of novel targeted therapies have significantly improved outcomes in R/R ALL. Blinatumomab, inotuzumab ozogamicin, and chimeric antigen receptor (CAR) T-cell therapy constitute new treatment modalities that are challenging the historical regimens and paving a new path for treating patients with R/R ALL.

Wang X, Yang J, Guo G, et al.
Novel lncRNA-IUR suppresses Bcr-Abl-induced tumorigenesis through regulation of STAT5-CD71 pathway.
Mol Cancer. 2019; 18(1):84 [PubMed] Article available free on PMC after 01/06/2020 Related Publications
BACKGROUND: Long noncoding RNAs (lncRNAs), defined as the transcripts longer than 200 nt without protein-coding capacity, have been found to be aberrantly expressed in diverse human diseases including cancer. A reciprocal translocation between chromosome 9 and 22 generates the chimeric Bcr-Abl oncogene, which is associated with several hematological malignancies. However, the functional relevance between aberrantly expressed lncRNAs and Bcr-Abl-mediated leukemia remains obscure.
METHODS: LncRNA cDNA microarray was used to identify novel lncRNAs involved in Bcr-Abl-mediated cellular transformation. To study the functional relevance of novel imatinib-upregulated lncRNA (IUR) family in Abl-induced tumorigenesis, Abl-transformed cell survival and xenografted tumor growth in mice was evaluated. Primary bone marrow transformation and in vivo leukemia transplant using lncRNA-IUR knockdown (KD) transgenic mice were further conducted to corroborate the role of lncRNA-IUR in Abl-induced tumorigenesis. Transcriptome RNA-seq, Western blot, RNA pull down and RNA Immunoprecipitation (RIP) were employed to determine the mechanisms by which lncRNA-IUR-5 regulates Bcr-Abl-mediated tumorigenesis.
RESULTS: We identified a conserved lncRNA-IUR family as a key negative regulator of Bcr-Abl-induced tumorigenesis. Increased expression of lncRNA-IUR was detected in both human and mouse Abl-transformed cells upon imatinib treatment. In contrast, reduced expression of lncRNA-IUR was observed in the peripheral blood lymphocytes derived from Bcr-Abl-positive acute lymphoblastic leukemia (ALL) patients compared to normal subjects. Knockdown of lncRNA-IUR remarkably promoted Abl-transformed leukemic cell survival and xenografted tumor growth in mice, whereas overexpression of lncRNA-IUR had opposite effects. Also, silencing murine lncRNA-IUR promoted Bcr-Abl-mediated primary bone marrow transformation and Abl-transformed leukemia cell survival in vivo. Besides, knockdown of murine lncRNA-IUR in transgenic mice provided a favorable microenvironment for development of Abl-mediated leukemia. Finally, we demonstrated that lncRNA-IUR-5 suppressed Bcr-Abl-mediated tumorigenesis by negatively regulating STAT5-mediated expression of CD71.
CONCLUSIONS: The results suggest that lncRNA-IUR may act as a critical tumor suppressor in Bcr-Abl-mediated tumorigenesis by suppressing the STAT5-CD71 pathway. This study provides new insights into functional involvement of lncRNAs in leukemogenesis.

Master S, Koshy N, Mansour R, Shi R
Effect of Stem Cell Transplant on Survival in Adult Patients With Acute Lymphoblastic Leukemia: NCDB Analysis.
Anticancer Res. 2019; 39(4):1899-1906 [PubMed] Related Publications
BACKGROUND: A retrospective analysis was performed to investigate the survival outcomes in adult acute lymphoblastic leukemia (ALL) based on treatment received.
MATERIALS AND METHODS: Data from 17,504 men and women (≥18 years of age) registered in the National Cancer Database who were diagnosed with ALL between 2004 and 2013 and had follow-up to the end of 2014, were analyzed. The primary predictor variable was treatment received, and overall survival was the outcome variable. Additional variables addressed and adjusted included gender, age, race, Charleston Comorbidity Index, level of education, income, insurance, distance traveled, facility type and diagnosing/treating facility.
RESULTS: The mean age of patients was 48.8 years with a standard deviation of 19.3 years. In multivariate analysis, after adjusting for secondary predictor variables, treatment modality was a statistically significant predictor of overall survival from ALL. Relative to patients who were treated with chemotherapy only, the patients who got chemotherapy and stem cell transplant had a decreased risk of mortality by 39%. Of the 5,409 patients between the ages of 18 and 39 years i.e. adolescent and young adults (AYA), no statistically significant survival difference was found between patients treated with stem cell transplant and those not.
CONCLUSION: Stem cell transplant led to improved survival for all age groups except the AYA.

Schittenhelm MM, Walter B, Tsintari V, et al.
Alternative splicing of the tumor suppressor ASPP2 results in a stress-inducible, oncogenic isoform prevalent in acute leukemia.
EBioMedicine. 2019; 42:340-351 [PubMed] Article available free on PMC after 01/06/2020 Related Publications
BACKGROUND: Apoptosis-stimulating Protein of TP53-2 (ASPP2) is a tumor suppressor enhancing TP53-mediated apoptosis via binding to the TP53 core domain. TP53 mutations found in cancers disrupt ASPP2 binding, arguing for an important role of ASPP2 in TP53-mediated tumor suppression. We now identify an oncogenic splicing variant, ASPP2κ, with high prevalence in acute leukemia.
METHODS: An mRNA screen to detect ASPP2 splicing variants was performed and ASPP2κ was validated using isoform-specific PCR approaches. Translation into a genuine protein isoform was evaluated after establishing epitope-specific antibodies. For functional studies cell models with forced expression of ASPP2κ or isoform-specific ASPP2κ-interference were created to evaluate proliferative, apoptotic and oncogenic characteristics of ASPP2κ.
FINDINGS: Exon skipping generates a premature stop codon, leading to a truncated C-terminus, omitting the TP53-binding sites. ASPP2κ translates into a dominant-negative protein variant impairing TP53-dependent induction of apoptosis. ASPP2κ is expressed in CD34+ leukemic progenitor cells and functional studies argue for a role in early oncogenesis, resulting in perturbed proliferation and impaired induction of apoptosis, mitotic failure and chromosomal instability (CIN) - similar to TP53 mutations. Importantly, as expression of ASPP2κ is stress-inducible it defines a novel class of dynamic oncogenes not represented by genomic mutations.
INTERPRETATION: Our data demonstrates that ASPP2κ plays a distinctive role as an antiapoptotic regulator of the TP53 checkpoint, rendering cells to a more aggressive phenotype as evidenced by proliferation and apoptosis rates - and ASPP2κ expression results in acquisition of genomic mutations, a first initiating step in leukemogenesis. We provide proof-of-concept to establish ASPP2κ as a clinically relevant biomarker and a target for molecule-defined therapy. FUND: Unrestricted grant support from the Wilhelm Sander Foundation for Cancer Research, the IZKF Program of the Medical Faculty Tübingen, the Brigitte Schlieben-Lange Program and the Margarete von Wrangell Program of the State Ministry Baden-Wuerttemberg for Science, Research and Arts and the Athene Program of the excellence initiative of the Eberhard-Karls University, Tübingen.

Fazio G, Massa V, Grioni A, et al.
First evidence of a paediatric patient with Cornelia de Lange syndrome with acute lymphoblastic leukaemia.
J Clin Pathol. 2019; 72(8):558-561 [PubMed] Related Publications
Cornelia de Lange syndrome (CdLS) is a rare autosomal-dominant genetic disorder characterised by prenatal and postnatal growth and mental retardation, facial dysmorphism and upper limb abnormalities. Germline mutations of cohesin complex genes

Lim WK, Fong CY, Li L, et al.
Extensive intracranial haemorrhage as a complication of acute lymphoblastic leukaemia with hyperleukocytosis.
J Clin Neurosci. 2019; 64:11-14 [PubMed] Related Publications
We report a rare case of distinctive extensive punctate intracranial haemorrhage associated with acute lymphoblastic leukaemia with hyperleukocytosis. A 7-year-old girl presented with hyperleukocytosis (white cell count 788.7 × 10

Niedźwiecki M, Budziło O, Adamkiewicz-Drożyńska E, et al.
J Immunol Res. 2019; 2019:2816498 [PubMed] Article available free on PMC after 01/06/2020 Related Publications
Regulatory T-cells (Tregs) are a very important subtype of lymphocytes when it comes to self-control in the human immunological system. Tregs are decisive not only in the protection against destruction of own tissues by autoimmune immunocompetent cells but also in the immunological answer to developing cancers. On the other hand, Tregs could be responsible for the progression of acute and chronic leukemias. In our study, we review publications available in the PUMED database concerning acute leukemia, with a particular emphasis on child's leukemias. The percentage of regulatory T-lymphocytes in peripheral blood and bone marrow was elevated compared to those in healthy individuals and correlated with progressive disease. Regulatory T-cells taken from children diagnosed with leukemia showed a higher suppressive capability, which was confirmed by detecting elevated levels of secreted IL-10 and TGF-beta. The possibility of pharmacological intervention in the self-control of the immunological system is now under extensive investigation in many human cancers. Presumably, Treg cells could be a vital part of targeted therapies. Routine Treg determination could be used to assess the severity of disease and prognosis in children with acute lymphoblastic leukemia. This proposition results from the fact that in some studies, higher percentage of Treg cells in peripheral blood was demonstrated. However, observations confirming these facts are scarce; thus, extrapolating them to the population of children with hematological malignancies needs to be verified in additional studies.

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