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Cancer Science Aug 2023Acute myeloid leukemia (AML) is a major leukemia with high mortality. Ferroptosis is an important regulator of cancers. However, the role of ferroptosis and its...
Acute myeloid leukemia (AML) is a major leukemia with high mortality. Ferroptosis is an important regulator of cancers. However, the role of ferroptosis and its regulatory mechanisms in AML remain largely unknown. In this study, we reported elevated brain and muscle ARNT-Like protein-1 (Bmal1) expression in AML patients and cell lines, and its upregulation indicated the poor survival of patients. The correlation analysis showed that Bmal1 expression was closely correlated with cytogenetics and the French-American-British subtypes, but was not correlated with age, gender and white blood cells. RSL3 reduced Bmal1 expression in HL-60 and NB4 cells. Malondialdehyde, total iron, Fe , glutathione and lipid peroxidation were examined to evaluate ferroptosis. Overexpression of Bmal1 repressed RSL3-induced ferroptosis in AML cells. Bmal1 recruited Enhancer of zeste homolog 2 (EZH2) to the Early B cell factor 3 (EBF3) promoter and enhanced its methylation, thus suppressing EBF3 expression. Moreover, the knockdown of Bmal1 sensitized AML cells to RSL3-induced ferroptosis, and it was counteracted by EBF3 knockdown. Furthermore, EBF3 bound to the Arachidonate 15-pipoxygenase (ALOX15) promoter to enhance its expression, and overexpression of EBF3 enhanced RSL3-induced ferroptosis dependent on ALOX5. We established a subcutaneous AML xenograft tumor model and reported that knockdown of Bmal1 and overexpression of EBF3 restrained AML growth by promoting ALOX15-mediated ferroptosis in vivo. Collectively, Bmal1 inhibits RSL3-induced ferroptosis by promoting EZH2-mediated EBF3 methylation and suppressing the expression of EBF3 and ALOX15, thus accelerating AML.
Topics: Humans; Ferroptosis; Cell Line, Tumor; Circadian Clocks; HL-60 Cells; Leukemia, Myeloid, Acute; Arachidonate 15-Lipoxygenase; Transcription Factors
PubMed: 37271497
DOI: 10.1111/cas.15875 -
Cancers Sep 2023Differentiation syndrome (DS) is a frequent and potentially life-threatening clinical syndrome first recognized with the advent of targeted therapeutics for acute... (Review)
Review
Differentiation syndrome (DS) is a frequent and potentially life-threatening clinical syndrome first recognized with the advent of targeted therapeutics for acute promyelocytic leukemia (APL). DS was subsequently observed more broadly with targeted therapeutics for acute myeloid leukemia (AML). DS is typically characterized by fever, dyspnea, hypotension, weight gain, pleural or pericardial effusions, and acute renal failure. The incidence in patients with APL ranges from 2 to 37%, with the wide variation likely attributed to different diagnostic criteria, use of prophylactic treatment, and different treatment regimens. Treatment with corticosteroids +/- cytoreductive therapy should commence as soon as DS is suspected to reduce DS-related morbidity and mortality. The targeted anti-leukemic therapy should be discontinued in patients with severe DS. Here, we discuss the pathogenesis of DS, clinical presentations, diagnostic criteria, management strategies, and implementation of prospective tracking on clinical trials.
PubMed: 37835461
DOI: 10.3390/cancers15194767 -
Pharmaceuticals (Basel, Switzerland) Nov 2023Acute myeloid leukemia (AML) is the second most common hematologic malignancy in children. The incidence of childhood AML is much lower than acute lymphoblastic leukemia... (Review)
Review
Acute myeloid leukemia (AML) is the second most common hematologic malignancy in children. The incidence of childhood AML is much lower than acute lymphoblastic leukemia (ALL), which makes childhood AML a rare disease in children. The role of genetic abnormalities in AML classification, management, and prognosis prediction is much more important than before. Disease classifications and risk group classifications, such as the WHO classification, the international consensus classification (ICC), and the European LeukemiaNet (ELN) classification, were revised in 2022. The application of the new information in childhood AML will be upcoming in the next few years. The frequency of each genetic abnormality in adult and childhood AML is different; therefore, in this review, we emphasize well-known genetic subtypes in childhood AML, including core-binding factor AML (CBF AML), (/11q23 rearrangement) AML, normal karyotype AML with somatic mutations, unbalanced cytogenetic abnormalities AML, rearrangement AML, and acute promyelocytic leukemia (APL). Current risk group classification, the management algorithm in childhood AML, and novel treatment modalities such as targeted therapy, immune therapy, and chimeric antigen receptor (CAR) T-cell therapy are reviewed. Finally, the indications of hematopoietic stem cell transplantation (HSCT) in AML are discussed.
PubMed: 38004478
DOI: 10.3390/ph16111614 -
Journal of Ethnopharmacology Nov 2023Processed from natural minerals, arsenic trioxide (ATO) as an ancient Chinese medicine has been used to treat diseases for over 2000 years. And it was applied to treat... (Review)
Review
ETHNOPHARMACOLOGICAL RELEVANCE
Processed from natural minerals, arsenic trioxide (ATO) as an ancient Chinese medicine has been used to treat diseases for over 2000 years. And it was applied to treat acute promyelocytic leukemia (APL) since the 1970s in China. Summarizing the clinical evidence of ATO in cancer is conducive to further understanding, development, and promotion of its pharmacological research.
AIM OF THE STUDY
It is the first time to comprehensively assess and summarize the evidence of ATO in cancer treatment via umbrella review.
MATERIALS AND METHODS
8 databases in English or Chinese from their inception to February 21, 2023 were searched by two reviewers separately and suitable meta-analyses (MAs) were included in this umbrella review. Their methodological quality and risk of bias were evaluated and data of outcomes was extracted and pooled again. The evidence certainty of pooled results was classified.
RESULTS
17 MAs with 27 outcomes and seven comparisons in three cancers were included in this umbrella review. However, their methodological quality was unsatisfactory with 6 MAs as low quality and 12 MAs as critically low quality. Their shortcomings were mainly focused on protocol, literature selecting, bias risk, small sample study bias, and conflicts of interest or funding. And they were all assessed as high risk in bias. It was suggested that ATO had an advantage in enhancing complete remission rate, event-free survival, and recurrence free survival and decreasing recurrence rate, cutaneous toxicity, hyper leukocyte syndrome, tretinoin syndrome, edema and hepatotoxicity in different comparisons of APL with low or moderate certainty. Besides, compared with transcatheter arterial chemoembolization (TACE) alone, ATO plus TACE also could improve objective response rate, disease control rate, survival rate (0.5, 1, 2, and 3-year) and life quality and reduce the level of alpha fetoprotein in primarily hepatocellular carcinoma with low or moderate certainty. However, no significant results were found in MM. Finally, key findings were as followed. ATO has potential broad-spectrum anticancer effects but the clinical transformation is rarely achieved. Route of administration may affect the antitumor effects of ATO. ATO can act synergistically in combination with a variety of antitumor therapies. The safety and drug resistance of ATO should be paid more attention to.
CONCLUSIONS
ATO may be a promising drug in anticancer treatment although earlier RCTs have dragged down the level of evidence. However, high-quality clinical trials are expected to explore its broad-spectrum anticancer effects, wide application, appropriate route of administration, and compound dosage form.
Topics: Humans; Arsenic Trioxide; Carcinoma, Hepatocellular; Liver Neoplasms; Chemoembolization, Therapeutic; Randomized Controlled Trials as Topic; Leukemia, Promyelocytic, Acute; Tretinoin
PubMed: 37290735
DOI: 10.1016/j.jep.2023.116734 -
Nature Communications Sep 2023The Boom syndrome helicase (BLM) unwinds a variety of DNA structures such as Guanine (G)-quadruplex. Here we reveal a role of RNF111/Arkadia and its paralog ARKL1, as...
The Boom syndrome helicase (BLM) unwinds a variety of DNA structures such as Guanine (G)-quadruplex. Here we reveal a role of RNF111/Arkadia and its paralog ARKL1, as well as Promyelocytic Leukemia Nuclear Bodies (PML NBs), in the regulation of ubiquitination and control of BLM protein levels. RNF111 exhibits a non-canonical SUMO targeted E3 ligase (STUBL) activity targeting BLM ubiquitination in PML NBs. ARKL1 promotes RNF111 localization to PML NBs through SUMO-interacting motif (SIM) interaction with SUMOylated RNF111, which is regulated by casein kinase 2 (CK2) phosphorylation of ARKL1 at a serine residue near the ARKL1 SIM domain. Upregulated BLM in ARKL1 or RNF111-deficient cells leads to a decrease of G-quadruplex levels in the nucleus. These results demonstrate that a CK2- and RNF111-ARKL1-dependent regulation of BLM in PML NBs plays a critical role in controlling BLM protein levels for the regulation of G-quadruplex.
Topics: Humans; Casein Kinase II; Promyelocytic Leukemia Nuclear Bodies; Promyelocytic Leukemia Protein; RecQ Helicases; Ubiquitination; Sumoylation; SUMO-1 Protein
PubMed: 37777511
DOI: 10.1038/s41467-023-41705-9 -
Cancers Jul 2023Tailored treatment with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has revolutionized the outcome of acute promyelocytic leukemia (APL) from a uniformly... (Review)
Review
Tailored treatment with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) has revolutionized the outcome of acute promyelocytic leukemia (APL) from a uniformly fatal disease to one of the most curable malignant diseases in humans. Due to its high efficacy, ATO/ATRA is the standard first-line therapy in younger adult, non-high-risk APL patients. However, early death is still a major issue in APL, particularly in older patients. Thus, rapid diagnostics, immediate access to ATRA-based therapy, and supportive care are of utmost importance. Nevertheless, challenging situations occur, particularly in patients excluded from controlled studies with clinical knowledge mainly based on case reports and registries. Besides the treatment of newly diagnosed patients, managing toxicities and complications remains challenging. This review discusses the approach to the treatment of APL in elderly and pediatric patients.
PubMed: 37509298
DOI: 10.3390/cancers15143637 -
Medical Science Monitor : International... Sep 2023Cinobufagin (CBF) is a bufadienolide, which is a major active ingredient of toad venom. In recent years, CBF has attracted increasing attention due to its highly potent...
Cinobufagin (CBF) is a bufadienolide, which is a major active ingredient of toad venom. In recent years, CBF has attracted increasing attention due to its highly potent and multiple pharmacological activities. To better understand the status of research on CBF, we collated recent studies on CBF to provide a valuable reference for clinical researchers and practitioners. According to reports, CBF exhibits extensive pharmacological properties, including antitumor, analgesic, cardioprotection, immunomodulatory, antifibrotic, antiviral, and antiprotozoal effects. Studies on the pharmacological activity of CBF have mainly focused on its anticancer activity. It has been demonstrated that CBF has a therapeutic effect on liver cancer, osteosarcoma, melanoma, colorectal cancer, acute promyelocytic leukemia, nasopharyngeal carcinoma, multiple myeloma, gastric cancer, and breast cancer. However, the direct molecular targets of CBF are currently unknown. In addition, there are few reports on toxicological and pharmacokinetic of CBF. Subsequent studies focusing on these aspects will help promote the development and application of CBF in clinical practice.
Topics: Humans; Amphibian Venoms; Bufanolides; Bone Neoplasms; Nasopharyngeal Neoplasms
PubMed: 37743616
DOI: 10.12659/MSM.940889 -
The Journal of Biological Chemistry Sep 2023Alternative lengthening of telomeres (ALTs) mechanism is activated in some somatic, germ cells, and human cancer cells. However, the key regulators and mechanisms of the...
Alternative lengthening of telomeres (ALTs) mechanism is activated in some somatic, germ cells, and human cancer cells. However, the key regulators and mechanisms of the ALT pathway remain elusive. Here we demonstrated that ZBTB40 is a novel telomere-associated protein and binds to telomeric dsDNA through its N-terminal BTB (BR-C, ttk and bab) or POZ (Pox virus and Zinc finger) domain in ALT cells. Notably, the knockout or knockdown of ZBTB40 resulted in the telomere dysfunction-induced foci and telomere lengthening in the ALT cells. The results also show that ZBTB40 is associated with ALT-associated promyelocytic leukemia nuclear bodies, and the loss of ZBTB40 induces the accumulation of the ALT-associated promyelocytic leukemia nuclear bodies in U2OS cells. Taken together, our results implicate that ZBTB40 is a key player of telomere protection and telomere lengthening regulation in human ALT cells.
Topics: Humans; Cell Line, Tumor; Telomere; Telomere Homeostasis; Protein Binding; DNA; Nuclear Bodies; DNA-Binding Proteins; Gene Knockdown Techniques; Gene Knockout Techniques; Apoptosis
PubMed: 37454741
DOI: 10.1016/j.jbc.2023.105053 -
Journal of Leukocyte Biology Sep 2023Advantages of cloned Hoxb8 neutrophil-like cells are discussed and contrasted with weaknesses of human HL-60 and PLB-985 neutrophil-like cell lines, and shared and...
Advantages of cloned Hoxb8 neutrophil-like cells are discussed and contrasted with weaknesses of human HL-60 and PLB-985 neutrophil-like cell lines, and shared and distinct features of primary murine and human neutrophils are summarized.
Topics: Animals; Mice; Humans; Neutrophils; HL-60 Cells; NADPH Oxidases
PubMed: 37403206
DOI: 10.1093/jleuko/qiad078 -
MedRxiv : the Preprint Server For... Oct 2023Coagulopathy and associated bleeding and venous thromboembolism (VTE) are major causes of morbidity and mortality in patients with acute leukemia. The underlying...
BACKGROUND
Coagulopathy and associated bleeding and venous thromboembolism (VTE) are major causes of morbidity and mortality in patients with acute leukemia. The underlying mechanisms of these complications have not been fully elucidated.
OBJECTIVES
To evaluate the associations between biomarker levels and bleeding and VTE in acute leukemia patients.
PATIENTS/METHOD
We examined plasma levels of activators, inhibitors and biomarkers of the coagulation and fibrinolytic pathways in patients ≥18 years with newly diagnosed acute leukemia compared to healthy controls. Multivariable regression models were used to examine the association of biomarkers with bleeding and VTE in acute leukemia patients. The study included 358 patients with acute leukemia (29 acute promyelocytic leukemia [APL], 253 non-APL acute myeloid leukemia [AML] and 76 acute lymphoblastic leukemia [ALL]), and 30 healthy controls.
RESULTS
Patients with acute leukemia had higher levels of extracellular vesicle (EV) tissue factor (TF) activity, phosphatidylserine-positive EVs, plasminogen activator inhibitor-1 (PAI-1), plasmin-antiplasmin complexes, cell-free DNA and lower levels of citrullinated histone H3-DNA complexes compared to healthy controls. APL patients had the highest levels of EVTF activity and the lowest levels of tissue plasminogen activator among the acute leukemia patients. There were 41 bleeding and 37 VTE events in acute leukemia patients. High EVTF activity was associated with increased risk of bleeding (sHR 2.30, 95%CI 0.99-5.31) whereas high PAI-1 was associated with increased risk of VTE (sHR 3.79, 95%CI 1.40-10.28) in these patients.
CONCLUSIONS
Our study shows alterations in several biomarkers in acute leukemia and identifies biomarkers associated with risk of bleeding and VTE.
PubMed: 37905148
DOI: 10.1101/2023.10.18.23297216