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Childhood Leukaemia
Acute Lymphocytic Leukemia: (ALL)
Acute Myeloid Leukemia: (AML)
Chronic Lymphocytic Leukemia: (CLL)
Chronic Myeloid Leukemia: (CML)
Hairy Cell Leukemia

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  • PubMed search for publications about Leukaemia - Limit search to: [Reviews]

    PubMed Central search for free-access publications about Leukaemia
    MeSH term: Leukemia
    International US National Library of Medicine
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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.

Riyahi N, Safaroghli-Azar A, Sheikh-Zeineddini N, et al.
Synergistic Effects of PI3K and c-Myc Co-targeting in Acute Leukemia: Shedding New Light on Resistance to Selective PI3K-δ Inhibitor CAL-101.
Cancer Invest. 2019; 37(7):311-324 [PubMed] Related Publications
Enthusiasms into the application of PI3K-δ inhibitor CAL-101 has been muted due to the over-activation of compensatory molecules. Our results delineated that c-Myc suppression using 10058-F4 enhanced CAL-101 cytotoxicity in less sensitive cells through different mechanisms based on p53 status; while CAL-101-plus-10058-F4 induced G1 arrest in wild-type p53-expressing leukemic cells, no conspicuous increase in G1 was noted in U937 cells harboring mutant p53. Conclusively, this study shed lights on the role of c-Myc oncoprotein in acute leukemia cells sensitivity to PI3K inhibitor and outlined that the combination of c-Myc inhibitor and CAL-101 may be a promising therapeutic approach in leukemia.

Guo Y
Clinical significance of serum MicroRNA-203 in patients with acute myeloid leukemia.
Bioengineered. 2019; 10(1):345-352 [PubMed] Related Publications
This study aimed to detect serum miR-203 expression levels in AML and explore its potential clinical significance. Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was performed to measure the serum miR-203 levels in 134 patients with AML and 70 healthy controls. The results demonstrated that serum miR-203 expression was significantly reduced in AML patients compared with healthy controls. Receiver operating characteristic curve (ROC) analysis revealed miR-203 could distinguish AML cases from normal controls. Low serum miR-203 levels were associated with worse clinical features, as well as poorer overall survival and relapse free survival of AML patients. Moreover, multivariate analysis confirmed low serum miR-203 expression to be an independent unfavorable prognostic predictor for AML. The bioinformatics analysis showed that the downstream genes and pathways of miR-203 was closely associated with tumorigenesis. Downregulation of miR-203 in AML cell lines upregulated the expression levels of oncogenic promoters such as CREB1, SRC and HDAC1. Thus, these findings demonstrated that serum miR-203 might be a promising biomarker for the diagnosis and prognosis of AML.

Wei AH, Roberts AW
Polyclonal Heterogeneity: The New Norm for Secondary Clinical Resistance to Targeted Monotherapy in Relapsed Leukemia?
Cancer Discov. 2019; 9(8):998-1000 [PubMed] Related Publications
In this issue, McMahon and colleagues demonstrate that secondary clinical resistance to the FLT3 inhibitor gilteritinib in relapsed acute myeloid leukemia is often polyclonal and commonly mediated by heterogeneous mutations that activate downstream RAS-MAPK pathways. These findings and recent data from others indicate that emergence of multiple clones, each with distinct mechanisms of resistance, is a common finding at secondary failure of single-agent-targeted therapies for relapsed leukemias.

Millett R, Aggarwal A, Tabbara I, Nassereddine S
Chronic Myeloid Leukemia as Secondary Malignancy Following the Treatment of Hodgkin Lymphoma: A Case Series.
Anticancer Res. 2019; 39(8):4333-4335 [PubMed] Related Publications
Secondary malignancies are relatively common and clinically important phenomena following both chemotherapy and radiotherapy. The majority of these cases are acute leukemias, the occurrence of which have been thoroughly documented and studied. More rarely, chronic myeloid leukemias (CML) may arise subsequent to treatment of a primary malignancy. Literature review on such developments following treatment of Hodgkin's Lymphoma (HL) is scant. Herein, the authors present three cases of CML diagnosed within five years of treatment initiation for Hodgkin's Lymphoma (HL); one of the three patients had CML with atypical variant carrying a rare mutation with BCR-JAK2 fusion.

Consoli ML, Romano A, Parrinello NL, et al.
Unusual Karyotype in Acute Myelomonocitic Leukemia: A Case Report.
Anticancer Res. 2019; 39(8):4329-4332 [PubMed] Related Publications
BACKGROUND/AIM: Acute myeloid leukemia is well characterized by chromosomal aberrations that correspond to various subtypes of acute leukemias. The t(8;21)(q22;q22) is a frequent chromosomal abnormality strongly associated with acute myeloblastic leukemia with maturation (AML-M2), but is rarely associated with other subtypes. Translocation involving a third chromosome could produce new genetic rearrangements that lead to leukemogenesis.
PATIENTS AND METHODS: Conventional cytogenetic analysis and fluorescence in situ hybridization (FISH) were performed to identify the karyotype. Reverse transcriptase polymerase chain reaction (RT-PCR) was used to detect the AML1/ETO transcript.
RESULTS/CONCLUSION: We herein report a novel rearrangement with a three-way translocation involving chromosomes 8, 21 and another unknown chromosome, in an 83-year-old female patient diagnosed as AML-M4, with an ALM1/ETO negative transcript. This is an uncommon case of AML-M4 with three-way translocation in a new variant of t(8;21) acute myeloid leukaemia. The detailed mechanism of different phenotype expression is unclear. Further study is needed to identify the leukemogenetic transformation resulting from t(8;21) translocation.

Itoh M, Okuhashi Y, Takahashi Y, et al.
Hypoxia Up-regulates HIF Expression While Suppressing Cell Growth and NOTCH Activity in Leukaemia Cells.
Anticancer Res. 2019; 39(8):4165-4170 [PubMed] Related Publications
AIM: To examine the influence of hypoxia on the in vitro growth of leukaemia cells and the activity of signalling proteins to better understand the pathophysiology of leukaemia cells in human bone marrow.
MATERIALS AND METHODS: Six human leukaemia cell lines were cultured under normoxic or hypoxic conditions. Cell growth, recovery of clonogenic cells, and the expression and activation of various signalling proteins were examined.
RESULTS: Hypoxia suppressed cell growth and the recovery of clonogenic cells. Moreover, hypoxia up-regulated hypoxia-inducible factor (HIF) 1α and HIF2α expression while suppressing the expression and activation of NOTCH1, mechanistic target of rapamycin kinase (mTOR) activation, and nuclear factor-kappa B (NF-κB) phosphorylation.
CONCLUSION: We found that hypoxia up-regulated HIF expression while it suppressed the self-renewal capacity of leukaemia cells, NOTCH activity, and expression of its down-stream signalling molecules, which differs from previous reports mentioning that HIF activates NOTCH signalling. Our findings serve to further elucidate the in vivo pathophysiology of leukaemia cells.

Shanafelt TD, Wang XV, Kay NE, et al.
Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia.
N Engl J Med. 2019; 381(5):432-443 [PubMed] Related Publications
BACKGROUND: Data regarding the efficacy of treatment with ibrutinib-rituximab, as compared with standard chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab, in patients with previously untreated chronic lymphocytic leukemia (CLL) have been limited.
METHODS: In a phase 3 trial, we randomly assigned (in a 2:1 ratio) patients 70 years of age or younger with previously untreated CLL to receive either ibrutinib and rituximab for six cycles (after a single cycle of ibrutinib alone), followed by ibrutinib until disease progression, or six cycles of chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab. The primary end point was progression-free survival, and overall survival was a secondary end point. We report the results of a planned interim analysis.
RESULTS: A total of 529 patients underwent randomization (354 patients to the ibrutinib-rituximab group, and 175 to the chemoimmunotherapy group). At a median follow-up of 33.6 months, the results of the analysis of progression-free survival favored ibrutinib-rituximab over chemoimmunotherapy (89.4% vs. 72.9% at 3 years; hazard ratio for progression or death, 0.35; 95% confidence interval [CI], 0.22 to 0.56; P<0.001), and the results met the protocol-defined efficacy threshold for the interim analysis. The results of the analysis of overall survival also favored ibrutinib-rituximab over chemoimmunotherapy (98.8% vs. 91.5% at 3 years; hazard ratio for death, 0.17; 95% CI, 0.05 to 0.54; P<0.001). In a subgroup analysis involving patients without immunoglobulin heavy-chain variable region (
CONCLUSIONS: The ibrutinib-rituximab regimen resulted in progression-free survival and overall survival that were superior to those with a standard chemoimmunotherapy regimen among patients 70 years of age or younger with previously untreated CLL. (Funded by the National Cancer Institute and Pharmacyclics; E1912 ClinicalTrials.gov number, NCT02048813.).

Wang J, Chen R, Lin X, et al.
New perspectives on treatment strategies for patient with acute myeloid leukemia and complex karyotype abnormalities after percutaneous coronary intervention: A case report.
Medicine (Baltimore). 2019; 98(30):e16586 [PubMed] Related Publications
RATIONALE: Acute myeloid leukemia (AML), in patients with coronary heart disease (CHD) and treated percutaneous coronary intervention (PCI), is rarely seen in clinic. There are few similar cases reported, and there are no evidence-based medicine guidelines for the treatment.
PATIENT CONCERNS: A 52-year-old man was diagnosed with coronary atherosclerotic heart disease in November 2011, and received a stent placement in the left anterior descending coronary artery 1 year later. One day after the surgery, his laboratory tests showed pancytopenia.
DIAGNOSES: Based on precise diagnosis of leukemia, namely cell morphology, immunology, cytogenetics, and molecular biological typing, the patient was diagnosed with AML-M2.
INTERVENTIONS: The patient received idarubicin with cytarabine in 1st cycles, and single cytarabine regimen was used in 2nd and 3rd cycles for the accumulative toxicity of idarubicin in postinduction chemotherapy. Meanwhile, staged-treatment strategy was implemented by using antiplatelet drugs during different chemotherapy phases, and personalized pharmaceutical care on the basis of the recognition of potential adverse effects of chemotherapy regimen.
OUTCOMES: Until now, the disease-free survival in the patient has been over 6 years, and he is still followed up in clinic.
LESSONS: Although leukemia accompanied with coronary heart disease, even after receiving the coronary stenting therapy is rarely seen in clinic, the treatment with antiplatelet drugs for post chemotherapy patients with coronary disease is necessary. Clinical pharmacists are supposed to be more proficient in developing personalized drug treatment strategies, especially maintaining the balance between the effect and the risk in difficult and complex cases.

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.

Yamasaki S, Nitta H, Kondo E, et al.
Effect of allogeneic hematopoietic cell transplantation for patients with T-prolymphocytic leukemia: a retrospective study from the Adult Lymphoma Working Group of the Japan Society for hematopoietic cell transplantation.
Ann Hematol. 2019; 98(9):2213-2220 [PubMed] Related Publications
Alemtuzumab is the treatment choice for patients with T-prolymphocytic leukemia (T-PLL). However, patients with T-PLL have a poor prognosis, and the option of allogeneic hematopoietic cell transplantation (HCT) remains controversial in these patients. This study aimed to analyze the outcomes of allogeneic HCT among patients with T-PLL to identify the potential clinical efficacy of allogeneic HCT. We retrospectively analyzed data from 20 patients with T-PLL, including five patients with complex chromosomal abnormalities at diagnosis who received an allogeneic HCT between 2000 and 2016. The median follow-up of survivors was 51 months in allogeneic HCT from human leukemia antigen (HLA)-matched donors. All five patients with complex chromosomal abnormalities died after allogeneic HCT. Our data suggest that allogeneic HCT from an HLA-matched donor can be considered for patients with T-PLL without complex chromosomal abnormalities. New treatment strategies of allogeneic HCT are required to improve the safety and efficacy of allografting in patients with T-PLL and complex chromosomal abnormalities. Potential approaches that identify patients with T-PLL and complex chromosomal abnormalities for allogeneic HCT with better disease control may allow identification of individuals who are suitable for allogeneic HCT.

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.

Lei H, Tu Y, Yang L, et al.
Quinacrine Depletes BCR-ABL and Suppresses Ph-Positive Leukemia Cells.
Cancer Invest. 2019; 37(6):242-252 [PubMed] Related Publications
Drug resistance to TKIs and the existance of CML leukemia stem cells is an urgent problem. In this study, we demonstrate that quinacrine (QC) induces apoptosis in BCR-ABL positive CML and acute lymphoblastic leukemia (ALL) cells. Interestingly, QC inhibits the colony formation of primary CD34

Wasilewska E, Kuziemski K, Niedoszytko M, et al.
Impairment of lung diffusion capacity-a new consequence in the long-term childhood leukaemia survivors.
Ann Hematol. 2019; 98(9):2103-2110 [PubMed] Free Access to Full Article Related Publications
Childhood leukaemia survivors (CLS) are known to have developed long-term impairment of lung function. The reasons for that complication are only partially known. The aims of this study were to assess pulmonary function in CLS and identify (1) risk factors and (2) clinical manifestations for the impairment of airflow and lung diffusion. The study group included 74 CLS: 46 treated with chemotherapy alone (HSCT-), 28 with chemotherapy and haematopoietic stem cell transplantation (HSCT+), and 84 healthy subjects (control group (CG)). Spirometry and diffusion limit of carbon monoxide (DLCO) tests were performed in all subjects. Ten (14%) survivors had restrictive, five (7%) had obstructive pattern, and 47 (66%) had reduced DLCO. The age at diagnosis, type of transplant, and type of conditioning regimen did not significantly affect the pulmonary function tests. The DLCO%pv were lower in CLS than in CG (p < 0.03) and in the HSCT+ than in the HSCT- survivors (p < 0.05). The pulmonary infection increased the risk of diffusion impairment (OR 5.1, CI 1.16-22.9, p = 0.019). DLCO was reduced in survivors who experienced CMV lung infection (p < 0.001). The main symptom of impaired lung diffusion was poor tolerance of exercise (p < 0.005). The lower lung diffusion capacity is the most frequent abnormality in CLS. HSCT and pulmonary infection, in particular with CMV infection, are strong risk factors for impairment of lung diffusion capacity in CLS. Clinical manifestation of DLCO impairment is poor exercise tolerance. A screening for respiratory abnormalities in CLS seems to be of significant importance.

Massimino M, Stella S, Tirrò E, et al.
Efficacy of Dasatinib in a Very Elderly CML Patient Expressing a Rare E13a3
Anticancer Res. 2019; 39(7):3949-3954 [PubMed] Related Publications
We report the case of an 89-year-old male diagnosed with chronic-phase CML and expressing a rare e13a3 BCR-ABL1 fusion transcript. His cytogenetic analysis showed the t(9;22) translocation generating the Philadelphia chromosome (Ph), with a multiplex RT-PCR detecting an atypical fragment. Using two primers complementary to exon 10 of BCR and exon 4 of ABL1, a larger PCR product was observed, where after Sanger sequencing, an e13a3 BCR-ABL1 transcript was revealed. Given the diagnosis, the patient received 100 mg of dasatinib every other day and was then monitored by measuring both hematological and cytogenetic parameters, while his BCR-ABL1 transcripts were examined by PCR and semi-nested-PCR. According to the 2013 European Leukemia Network criteria, after six months of dasatinib the patient's response was classified as warning as he displayed 20% of Philadelphia-positive metaphases. Sequencing of the ABL1 catalytic domain did not detect point mutations. A complete cytogenetic response was achieved after one year of dasatinib. However, semi-nested-PCR confirmed the presence of the e13a3 BCR-ABL1 fusion transcript that has persisted up to the latest follow-up visit.

Tirrò E, Massimino M, Stella S, et al.
Efficacy of Nilotinib in a CML Patient Expressing the Three-way Complex Variant Translocation t(2;9;22).
Anticancer Res. 2019; 39(7):3893-3899 [PubMed] Related Publications
BACKGROUND/AIM: Chronic myelogenous leukemia (CML) is characterized by the presence of the Philadelphia chromosome, resulting from the reciprocal translocation involving chromosomes 9 and 22. About 5-10% of newly diagnosed patients in chronic-phase (CP) CML show complex additional chromosomal aberrations (ACA), that may involve one or more chromosomes in addition to 9 and 22. Data concerning the prognostic significance of ACA in CP-CML subjects at diagnosis are controversial. Furthermore, there is no evidence showing that selection of imatinib (IM) or second-generation tyrosine kinase inhibitors (2G-TKI) would be of benefit for these patients.
CASE REPORT: We report the three-way complex variant translocation t(2;9;22) in a CP-CML patient. Conventional cytogenetic analysis was employed to identify the ACA. Multiplex reverse transcription-PCR was used to identify the BCR-ABL1 transcript and its levels were measured using quantitative real-time-PCR. This rare ACA t(2;9;22) in our young patient displayed primary resistance to IM, but was responsive to second-line treatment with nilotinib.
CONCLUSION: CP-CML patients exhibiting this rare aberration at diagnosis may benefit from a 2G-TKI therapy compared to IM.

Ivanova D, Zhelev Z, Semkova S, et al.
Resveratrol Modulates the Redox-status and Cytotoxicity of Anticancer Drugs by Sensitizing Leukemic Lymphocytes and Protecting Normal Lymphocytes.
Anticancer Res. 2019; 39(7):3745-3755 [PubMed] Related Publications
BACKGROUND/AIM: The study is directed to the effect of resveratrol on the redox-status and viability of leukemic and normal lymphocytes, as well as its ability to sensitize leukemic lymphocytes to anticancer drugs.
MATERIALS AND METHODS: Cytotoxicity was analyzed by trypan blue staining, apoptosis - by Annexin V test, and oxidative stress - by the intracellular levels of reactive oxygen species (ROS) and protein-carbonyl products.
RESULTS: Incubation of resveratrol in combination with the majority of anticancer drugs resulted in higher toxicity than resveratrol or drug alone. In the case of leukemic lymphocytes treated with barasertib and everolimus in the presence of resveratrol, synergistic cytotoxicity was accompanied by strong induction of apoptosis, increased levels of hydroperoxides and insignificant changes in protein-carbonyl products. None of these parameters changed in normal lymphocytes.
CONCLUSION: Resveratrol is a promising supplementary compound for anticancer therapy, that may allow reduction of the therapeutic doses of barasertib and everolimus, minimizing their side-effects.

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.

Savona MR, Rathmell JC
Mitochondrial Homeostasis in AML and Gasping for Response in Resistance to BCL2 Blockade.
Cancer Discov. 2019; 9(7):831-833 [PubMed] Related Publications
Understanding resistance to BCL2 inhibition is a critical scientific and clinical challenge. In this issue of

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.

Boileau M, Shirinian M, Gayden T, et al.
Mutant H3 histones drive human pre-leukemic hematopoietic stem cell expansion and promote leukemic aggressiveness.
Nat Commun. 2019; 10(1):2891 [PubMed] Free Access to Full Article Related Publications
Our ability to manage acute myeloid leukemia (AML) is limited by our incomplete understanding of the epigenetic disruption central to leukemogenesis, including improper histone methylation. Here we examine 16 histone H3 genes in 434 primary AML samples and identify Q69H, A26P, R2Q, R8H and K27M/I mutations (1.6%), with higher incidence in secondary AML (9%). These mutations occur in pre-leukemic hematopoietic stem cells (HSCs) and exist in the major leukemic clones in patients. They increase the frequency of functional HSCs, alter differentiation, and amplify leukemic aggressiveness. These effects are dependent on the specific mutation. H3K27 mutation increases the expression of genes involved in erythrocyte and myeloid differentiation with altered H3K27 tri-methylation and K27 acetylation. The functional impact of histone mutations is independent of RUNX1 mutation, although they at times co-occur. This study establishes that H3 mutations are drivers of human pre-cancerous stem cell expansion and important early events in leukemogenesis.

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.

Rodríguez-Veiga R, Montesinos P, Boluda B, et al.
Incidence and outcome of invasive fungal disease after front-line intensive chemotherapy in patients with acute myeloid leukemia: impact of antifungal prophylaxis.
Ann Hematol. 2019; 98(9):2081-2088 [PubMed] Related Publications
Few reports analyze the incidence and clinical outcome of invasive fungal disease (IFD) in patients with newly diagnosed acute myeloid leukemia (AML) undergoing intensive chemotherapy, and thus the impact of different antifungal prophylactic regimens remains unclear. We analyze the incidence and clinical outcome of IFD in a large series of adult AML patients undergoing front-line intensive induction and consolidation chemotherapy between 2004 and 2015 in a single institution. Three antifungal prophylaxis regimens were given (2004-2005 oral fluconazole, 2006-2012 intravenous itraconazole, and 2013-2015 voriconazole). Overall, 285 patients and 589 intensive chemotherapy episodes were assessed (47%) (induction courses 47% and consolidation 53%). The median age was 51 years (range, 17-65). We observed 56 (10%) episodes of IFD. According to the EORTC 2008 criteria, IFD was classified as possible (29, 52%), probable (17, 30%), and proven (10, 18%). Possible/probable/proven IFD rate was significantly lower during HiDAC consolidation as compared to any anthracycline-containing chemotherapy courses (2% vs. 11%, P = 0.001), and under voriconazole prophylaxis as compared to itraconazole and fluconazole (6% vs. 11% vs. 15%, P = 0.007), and the multivariate analysis showed that they were independent risk factors. Patients under voriconazole prophylaxis had shorter hospitalization duration and less frequent use of empirical or directed antifungal therapy. In conclusion, IFD was a frequent complication during upfront intensive chemotherapy courses for adult AML patients. This retrospective study shows that voriconazole prophylaxis was feasible and associated with a lower risk of IFD compared with intravenous itraconazole or oral fluconazole schedules.

Chen KTJ, Gilabert-Oriol R, Bally MB, Leung AWY
Recent Treatment Advances and the Role of Nanotechnology, Combination Products, and Immunotherapy in Changing the Therapeutic Landscape of Acute Myeloid Leukemia.
Pharm Res. 2019; 36(9):125 [PubMed] Free Access to Full Article Related Publications
Acute myeloid leukemia (AML) is the most common acute leukemia that is becoming more prevalent particularly in the older (65 years of age or older) population. For decades, "7 + 3" remission induction therapy with cytarabine and an anthracycline, followed by consolidation therapy, has been the standard of care treatment for AML. This stagnancy in AML treatment has resulted in less than ideal treatment outcomes for AML patients, especially for elderly patients and those with unfavourable profiles. Over the past two years, six new therapeutic agents have received regulatory approval, suggesting that a number of obstacles to treating AML have been addressed and the treatment landscape for AML is finally changing. This review outlines the challenges and obstacles in treating AML and highlights the advances in AML treatment made in recent years, including Vyxeos®, midostaurin, gemtuzumab ozogamicin, and venetoclax, with particular emphasis on combination treatment strategies. We also discuss the potential utility of new combination products such as one that we call "EnFlaM", which comprises an encapsulated nanoformulation of flavopiridol and mitoxantrone. Finally, we provide a review on the immunotherapeutic landscape of AML, discussing yet another angle through which novel treatments can be designed to further improve treatment outcomes for AML patients.

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.

Bell CC, Fennell KA, Chan YC, et al.
Targeting enhancer switching overcomes non-genetic drug resistance in acute myeloid leukaemia.
Nat Commun. 2019; 10(1):2723 [PubMed] Free Access to Full Article Related Publications
Non-genetic drug resistance is increasingly recognised in various cancers. Molecular insights into this process are lacking and it is unknown whether stable non-genetic resistance can be overcome. Using single cell RNA-sequencing of paired drug naïve and resistant AML patient samples and cellular barcoding in a unique mouse model of non-genetic resistance, here we demonstrate that transcriptional plasticity drives stable epigenetic resistance. With a CRISPR-Cas9 screen we identify regulators of enhancer function as important modulators of the resistant cell state. We show that inhibition of Lsd1 (Kdm1a) is able to overcome stable epigenetic resistance by facilitating the binding of the pioneer factor, Pu.1 and cofactor, Irf8, to nucleate new enhancers that regulate the expression of key survival genes. This enhancer switching results in the re-distribution of transcriptional co-activators, including Brd4, and provides the opportunity to disable their activity and overcome epigenetic resistance. Together these findings highlight key principles to help counteract non-genetic drug resistance.

Minuesa G, Albanese SK, Xie W, et al.
Small-molecule targeting of MUSASHI RNA-binding activity in acute myeloid leukemia.
Nat Commun. 2019; 10(1):2691 [PubMed] Free Access to Full Article Related Publications
The MUSASHI (MSI) family of RNA binding proteins (MSI1 and MSI2) contribute to a wide spectrum of cancers including acute myeloid leukemia. We find that the small molecule Ro 08-2750 (Ro) binds directly and selectively to MSI2 and competes for its RNA binding in biochemical assays. Ro treatment in mouse and human myeloid leukemia cells results in an increase in differentiation and apoptosis, inhibition of known MSI-targets, and a shared global gene expression signature similar to shRNA depletion of MSI2. Ro demonstrates in vivo inhibition of c-MYC and reduces disease burden in a murine AML leukemia model. Thus, we identify a small molecule that targets MSI's oncogenic activity. Our study provides a framework for targeting RNA binding proteins in cancer.

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.

Ye J, Luo D, Yu J, Zhu S
Transcriptome analysis identifies key regulators and networks in Acute myeloid leukemia.
Hematology. 2019; 24(1):487-491 [PubMed] Related Publications
OBJECTIVES: Acute myeloid leukemia (AML) is a heterogeneous and highly recurrent hematological malignancy. Studies have shown an association between microRNAs and drive genes in AMLs. However, the regulatory roles of miRNAs in AML and how they act on downstream targets and the signaling pathway has been little studied.
METHODS: As to understand the mechanism of mRNA-miRNA interaction in the blood malignancy from a large scale of transcriptomic sequencing studies, we applied a comprehensive miRNA-mRNA association, co-expression gene network and ingenuity pathway analysis using TCGA AML datasets.
RESULTS: Our results showed that his-mir-335 was a critical regulatory of homeobox A gene family. PBX3, KAT6A, MEIS1, and COMMD3-BMI1 were predicted as top transcription regulators in the regulatory network of the HOXA family. The most significantly enriched functions were cell growth, proliferation, and survival in the mRNA-miRNA network.
CONCLUSION: Our work revealed that regulation of the HOXA gene family and its regulation played an important role in the development of AML.

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