Human Leukemia Research Articles

Reprogramming of RNA m6A Modification Is Required for Acute Myeloid Leukemia Development.

Hematopoietic homeostasis is maintained by hematopoietic stem cells (HSCs), and it is tightly controlled at multiple levels to sustain the self-renewal capacity and differentiation potential of HSCs. Dysregulation of self-renewal and differentiation of HSCs leads to the development of hematologic diseases, including acute myeloid leukemia (AML). Thus, understanding the underlying mechanisms of HSC maintenance and the development of hematologic malignancies is one of the fundamental scientific endeavors in stem cell biology. N 6-methyladenosine (m6A) is a common modification in mammalian messenger RNAs (mRNAs) and plays important roles in various biological processes. In this study, we performed a comparative analysis of the dynamics of the RNA m6A methylome of hematopoietic stem and progenitor cells (HSPCs) and leukemia-initiating cells (LICs) in AML. We found that RNA m6A modification regulates the transformation of long-term HSCs into short-term HSCs and determines the lineage commitment of HSCs. Interestingly, m6A modification leads to reprogramming that promotes cellular transformation during AML development, and LIC-specific m6A targets are recognized by different m6A readers. Moreover, the very long chain fatty acid transporter ATP-binding cassette subfamily D member 2 (ABCD2) is a key factor that promotes AML development, and deletion of ABCD2 damages clonogenic ability, inhibits proliferation, and promotes apoptosis of human leukemia cells. This study provides a comprehensive understanding of the role of m6A in regulating cell state transition in normal hematopoiesis and leukemogenesis, and identifies ABCD2 as a key factor in AML development.

HLA-A*24 Increases the Risk of HTLV-1-Associated Myelopathy despite Reducing HTLV-1 Proviral Load.

Increased human T-cell leukemia virus type 1 (HTLV-1) proviral load (PVL) is a significant risk factor for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is controversy surrounding whether HTLV-1-specific cytotoxic T lymphocytes (CTLs) are beneficial or harmful to HAM/TSP patients. Recently, HTLV-1 Tax 301-309 has been identified as an immunodominant epitope restricted to HLA-A*2402. We investigated whether HLA-A*24 reduces HTLV-1 PVL and the risk of HAM/TSP using blood samples from 152 HAM/TSP patients and 155 asymptomatic HTLV-1 carriers. The allele frequency of HLA-A*24 was higher in HAM/TSP patients than in asymptomatic HTLV-1 carriers (72.4% vs. 58.7%, odds ratio 1.84), and HLA-A*24-positive patients showed a 42% reduction in HTLV-1 PVL compared to negative patients. Furthermore, the PVL negatively correlated with the frequency of Tax 301-309-specific CTLs. These findings are opposite to the effects of HLA-A*02, which reduces HTLV-1 PVL and the risk of HAM/TSP. Therefore, we compared the functions of CTLs specific to Tax 11-19 or Tax 301-309, which are immunodominant epitopes restricted to HLA-A*0201 or HLA-A*2402, respectively. The maximum responses of these CTLs were not different in the production of IFN-γ and MIP-1β or in the expression of CD107a-a marker for the degranulation of cytotoxic molecules. However, Tax 301-309-specific CTLs demonstrated 50-fold higher T-cell avidity than Tax 11-19-specific CTLs, suggesting better antigen recognition at low expression levels of the antigens. These findings suggest that HLA-A*24, which induces sensitive HTLV-1-specific CTLs, increases the risk of HAM/TSP despite reducing HTLV-1 PVL.

Green synthesis of ultrafine gold nanoparticles from sweet flag (Acorus calamus) for effective anti-leukemic, anti-urolithiatic and in silico docking studies

Gold nanoparticles (AuNPs) are emerging effective biomaterials which play a vital role in the biodiversity research area due to their biocompatibility, and less toxic nature. The AuNPs of various sizes and shapes have vibrant optical features that can be utilized for a variety of imaging and therapeutic applications. Acorus calamus (A. calamus) has been used in traditional medical systems as a general tonic for centuries. It is thought to have potential benefits in the treatment of digestive disorders and respiratory problems. In Kerala, newborns were given a nanogram of (A. calamus) rhizome paste to increase oral cleanliness and improve their health and immunity. This prompted us to produce AuNPs by A. calamus and to explore their concealed pharmacological properties. In this work, we used a simple sonication method to synthesise blue-coloured AuNPs using sweet flag (A. calamus) extract, which acted as a stabilising and reducing agent at ambient temperature. The formation and morphology of the AC-AuNPs was confirmed by XRD, TEM, EDX, FT-IR and UV–vis spectral techniques. Anti-leukemic and anti-urolithiatic activities of the AC-AuNPs were also investigated. The anti-leukemic results revealed cytomorphological changes like cancer cell membrane lyses and coiling in Human myelogenous leukemia cells (K562) and exhibited IC50 at a concentration of 41.45 µg/mL. Furthermore, in vitro DNA binding assay of AC-AuNPs with calf-thymus were conducted. The anti-urolithiatic activity of AC-AuNPs suggests a dose-dependent suppression of calcium oxalate method (COM) crystals nucleation and aggregation. These results suggest that AC-AuNPs have potent antileukemic and anti-urolithiatic activities. In silico docking results revealed that eugenol, α-asarone and calamenene possess good binding scores with myeloid cell surface antigen (CD33) and estrogen receptors, respectively. In vitro anticancer and DNA binding studies have endorsed the capping nature of AC-AuNPs by these phytoconstituents, which is validated by docking analysis.

Additional considerations in cancer cell radioresistance, integrin αvβ3 and thyroid hormones

ABSTRACT Background The existence of a functional relationship between a certain thyroid hormone analogue and cancer cell radioresistance has been shown by Leith and coworkers. The hormone analogue with relevance to malignant cells’ radioresistance is tetraiodothyroacetic acid (tetrac). Tetrac is the deaminated derivative of L-thyroxine (T4), the principal product of the thyroid gland. Preclinical studies demonstrated that tetrac and chemically modified tetrac (CMT), e.g. a fluorobenzyl-conjugated tetrac analogue, restores radiosensitivity in certain radioresistant tumor cells. Due to their molecular, physico-chemical, and biological properties, actions of CMT analogues are believed to be initiated at the thyroid hormone analogue receptor site on plasma membrane integrin αvβ3. Objective To explore possible molecular mechanisms of the potentially therapeutically beneficial effect of CMT on cancer cells’ sensitivity to radiation, we analyzed actions of CMT analogues on expression of selected sets of genes that have been previously implicated in radioresistance of malignant cells. Discussion and conclusions In the current study, we report that genome-wide gene expression profiling analysis of human glioblastoma (GBM) and acute myelocytic leukemia (AML) cell lines exposed in vitro to noncytotoxic doses of CMT has identified decreased expression of discrete trios of genes each of which was previously linked to cancer cells’ radioresistance. Following the CMT treatment in AML cells, expression of PARP9, PARP15 and STAT3 genes was significantly reduced, while in GBM cells, expression of PRKDC, EGFR and CCNDI was significantly decreased by the drug. Notably, a broader spectrum of genes implicated in cancer cells’ radioresistance was observed in primary patient-derived GBM cells after the CMT treatment. Extensive additional experimental and clinical studies are indicated, including analyses of individual patient tumor genomics and of an array of different tumor types to define the sub-sets of tumors manifesting radioresistance in which tetrac-based agents may be expected to enhance therapeutic effects of radiation.

Novel centratherin derivatives: Molecular docking design, asymmetric synthesis, and antitumoral activity

Centratherin is a sesquiterpene lactone that has the potential to inhibit target proteins for cancer therapy, such as the inflammatory mediator NF-κB. Indoles also exhibit antitumoral activity and can modulate the NF-κB signaling pathway. Here we describe a molecular-docking guided semi-synthesis of indole-containing centratherin derivatives. In silico studies indicated that these compounds have high affinity to NF-κB and do not present toxicity or carcinogenicity. Two enantiomeric series of indole-centratherin hybrids were synthesized in three steps with good yields and ee, employing an organocatalyzed Friedel-Crafts alkylation as a key step. The compounds were evaluated against human leukemia K562 cells and showed promising antitumoral activities with IC50 ranging from 0.49 to 7.83 μM.

BM7, a derivative of benzofuran, effectively fights cancer by promoting cancer cell apoptosis and impacting IL-6 levels

The BM7 compound, a bromo derivative of methyl 6-acetyl-5-hydroxy-2-methyl-1-benzofuran-3-carboxylate, was previously identified as cytotoxic to human leukaemia cells (K562 and HL60) and human cervical cancer (HeLa), while showing no toxicity to non-cancerous primary endothelial cells (HUVEC). In this study, we present the first demonstration of BM7's anticancer efficacy in vivo using a mouse chronic myeloid leukaemia xenograft model. Administered intraperitoneally in a mixture of 10% Solutol HS 15/10% ethanol, BM7 exhibited no visible toxicity and significantly reduced tumor weight, comparable to standard drugs imatinib and hydroxyurea. Further supporting its anticancer potential, a multi-model in vitro study involving seven human cancer cell lines revealed the most promising responses in colon cancer (SW480, SW620, HCT116), liver cancer (HEPG2), and breast adenocarcinoma (MDA-MB-231) cells. BM7 demonstrated multifaceted anticancer mechanisms, inducing apoptosis while elevating reactive oxygen species (ROS) levels and suppressing interleukin-6 (IL-6) release in these cell lines. These findings position BM7 as a candidate of significant interest for cancer therapy. Its ability to not only induce apoptosis but also modulate cellular processes such as ROS levels and immune responses, specifically IL-6 suppression, makes BM7 a versatile and promising agent for further exploration in the realm of cancer treatment.

Synthesis of a New Class of β-Carbonyl Selenides Functionalized with Ester Groups with Antioxidant and Anticancer Properties-Part II.

A series of phenyl β-carbonyl selenides with o-ester functionality substituted on the oxygen atom with chiral and achiral alkyl groups was synthesized. All compounds are the first examples of this type of organoselenium derivatives with an ester substituent in the ortho position. The obtained derivatives were tested as antioxidants and anticancer agents to see the influence of an ester functionality on the bioactivity of β-carbonyl selenides by replacing the o-amide group with an o-ester group. The best results as an antioxidant agent were observed for O-((1R,2S,5R)-(-)-2-isopropyl-5-methylcyclohexyl)-2-((2-oxopropyl)selanyl)benzoate. The most cytotoxic derivative against breast cancer MCF-7 cell lines was O-(methyl)-2-((2-oxopropyl)selanyl)benzoate and against human promyelocytic leukemia HL-60 was O-(2-pentyl)-2-((2-oxopropyl)selanyl)benzoate.

Comparable efficacy of oral bendamustine versus intravenous administration in treating hematologic malignancies.

The purpose of this study was to analyze potential differences in antitumor efficacy and pharmacokinetics between intravenous (IV) bendamustine and a novel orally administered (PO) bendamustine agent that is utilizing the beneficial properties of superstaturated solid dispersions formulated in nanoparticles. Pharmacokinetics of IV versus PO bendamustine were determined by analysis of plasma samples collected from NSG mice treated with either IV or PO bendamustine. Plasma samples were analyzed using liquid chromatography-mass spectrometry following a liquid-liquid extraction to determine peak bendamustine concentration, area under the concentration-time curve, and the half-life in-vivo. In-vitro cytotoxicity of bendamustine against human non-Hodgkin Burkitt's Lymphoma (Raji), multiple myeloma (MM.1s), and B-cell acute lymphoblastic leukemia (RS4;11) cell lines was determined over time using MTS assays. Luciferase-tagged versions of the aforementioned cell lines were used to determine in-vivo bendamustine cytotoxicity of IV versus PO bendamustine at two different doses. Bendamustine at a high dose in-vitro causes cell death. There was no significant difference in antitumor activity between IV and novel PO bendamustine at a physiologically relevant concentration in all three xenograft models. In-vivo pharmacokinetics showed the oral bioavailability of bendamustine in mice to be 51.4%. The novel oral bendamustine agent tested exhibits good oral bioavailability and systemic exposure for in-vivo antitumor efficacy comparable to IV bendamustine. An oral bendamustine formulation offers exciting clinical potential as an additional method of administration for bendamustine and warrants further evaluation in clinical studies.

Mechanisms Underlying the Development of Murine T-Cell Lymphoblastic Lymphoma/Leukemia Induced by Total-Body Irradiation.

Exposure to ionizing radiation is associated with an increased risk of hematologic malignancies in myeloid and lymphoid lineages in humans and experimental mice. Given that substantial evidence links radiation exposure with the risk of hematologic malignancies, it is imperative to deeply understand the mechanisms underlying cellular and molecular changes during the latency period between radiation exposure and the emergence of fully transformed malignant cells. One experimental model widely used in the field of radiation and cancer biology to study hematologic malignancies induced by radiation exposure is mouse models of radiation-induced thymic lymphoma. Murine radiation-induced thymic lymphoma is primarily driven by aberrant activation of Notch signaling, which occurs frequently in human precursor T-cell lymphoblastic lymphoma (T-LBL) and T-cell lymphoblastic leukemia (T-ALL). Here, we summarize the literature elucidating cell-autonomous and non-cell-autonomous mechanisms underlying cancer initiation, progression, and malignant transformation in the thymus following total-body irradiation (TBI) in mice.

Dynamics of nucleoplasm in human leukemia cells: A thrust towards designing anti-leukemic agents

The human inosine monophosphate dehydrogenase (hIMPDH) is a metabolic enzyme that possesses a unique ability to self-assemble into higher-order structures, forming cytoophidia. The hIMPDH II isoform is more active in chronic myeloid leukemia (CML) cancer cells, making it a promising target for anti-leukemic therapy. However, the structural details and molecular mechanisms of the dynamics of hIMPDHcytoophidia assembly in vitro need to be better understood, and it is crucial to reconstitute the computational nucleoplasm model with cytophilic-like polymers in vitro to characterize their structure and function. Finally, a computational model and its dynamics of the nucleoplasm for CML cells have been proposed in this short review. This research on nucleoplasm aims to aid the scientific community's understanding of how metabolic enzymes like hIMPDH function in cancer and normal cells.However, validating and justifying the computational results from modeling and simulation with experimental data is essential. The new insights gained from this research could explain the structure/topology, geometrical, and electronic consequences of hIMPDH inhibitors on leukemic and normal cells. They could lead to further advancements in the knowledge of nucleoplasmic chemical reaction dynamics.

Evaluating the therapeutic potential of amygdalin: Cytotoxic and antimicrobial properties

Leukemia is an incurable disease; it exhibits strong resistance to chemotherapy and other therapies, and it represents the most common childhood cancer and mortality. The cytotoxic of amygdalin (AMG) against the cell line of human monocytic leukemia (THP-1) was recorded, before determining other pharmacological effects. The cells were exposed to AMG for 24 hr at 37°C at different concentrations, the cytotoxic effect was determined via the MTT assay. The cells and the supernatant were collected for analyzing the oxidant/antioxidant status, apoptotic markers, and anti-microbial activity. Results showed a marked anti-proliferative cytotoxic effect of AMG which is concentration and time-dependent, the lipid peroxidation content was significantly decreased while the total thiol was increased in the treated cell line, significant up-regulation of Caspase-3 (Cas-3) and Bcl-2-associated X protein (BAX) and down-regulation of B-cell lymphoma 2 (Bcl-2). Furthermore, The bacterial activity was detected via Minimum Inhibitory Concentration (MIC), Minimum Bactericidal Concentration (MBC), and Disc Diffusion assays, while the antifungal evaluation was done by the Minimum Fungicidal Concentration (MFC). Antimicrobial experiments revealed that AMG exerted potent, broad-spectrum antimicrobial effects toward a diversity of dangerously infecting pathogens. In conclusion; the prevailing research suggests that AMG is an effective anticarcinogenic and antimicrobial substance. The utilization of AMG subsequently in masks or wound dressings to prevent bacterial & fungal infections, including mucormycosis following COVID-19, as well as infections caused by penicillium and aspergillus, is a highly effective strategy in combating resistant microorganisms.

Ergone Derivatives from the Deep-Sea-Derived Fungus Aspergillus terreus YPGA10 and 25,28-Dihydroxyergone-Induced Apoptosis in Human Colon Cancer SW620 Cells.

Ten new ergone derivatives (1-10) and five known analogues (11-15) were isolated from the deep-sea-derived fungus Aspergillus terreus YPGA10. The structures including the absolute configurations were established by detailed analysis of the NMR spectroscopic data, HRESIMS, ECD calculation, and coupling constant calculation. All the structures are characterized by a highly conjugated 25-hydroxyergosta-4,6,8(14),22-tetraen-3-one nucleus. Structurally, compound 2 bearing a 15-carbonyl group and compounds 5-7 possessing a 15β-OH/OCH3 group are rarely encountered in ergone derivatives. Bioassay results showed that compounds 1 and 11 demonstrated cytotoxic effects on human colon cancer SW620 cells with IC50 values of 8.4 and 3.1 μM, respectively. Notably, both compounds exhibited negligible cytotoxicity on the human normal lung epithelial cell BEAS-2B. Compound 11 was selected for preliminary mechanistic study and was found to inhibit cell proliferation and induce apoptosis in human colon cancer SW620 cells. In addition, compound 1 displayed cytotoxic activity against five human leukemia cell lines with IC50 values ranging from 5.7 to 8.9 μM. Our study demonstrated that compound 11 may serve as a potential candidate for the development of anticolorectal cancer agents.

Cytotoxic Effects of Doxorubicin on Cancer Cells and Macrophages Depend Differently on the Microcarrier Structure.

Microparticles are versatile carriers for controlled drug delivery in personalized, targeted therapy of various diseases, including cancer. The tumor microenvironment contains different infiltrating cells, including immune cells, which can affect the efficacy of antitumor drugs. Here, prototype microparticle-based systems for the delivery of the antitumor drug doxorubicin (DOX) were developed, and their cytotoxic effects on human epidermoid carcinoma cells and macrophages derived from human leukemia monocytic cells were compared in vitro. DOX-containing calcium carbonate microparticles with or without a protective polyelectrolyte shell and polyelectrolyte microcapsules of about 2.4-2.5 μm in size were obtained through coprecipitation and spontaneous loading. All the microstructures exhibited a prolonged release of DOX. An estimation of the cytotoxicity of the DOX-containing microstructures showed that the encapsulation of DOX decreased its toxicity to macrophages and delayed the cytotoxic effect against tumor cells. The DOX-containing calcium carbonate microparticles with a protective polyelectrolyte shell were more toxic to the cancer cells than DOX-containing polyelectrolyte microcapsules, whereas, for the macrophages, the microcapsules were most toxic. It is concluded that DOX-containing core/shell microparticles with an eight-layer polyelectrolyte shell are optimal drug microcarriers due to their low toxicity to immune cells, even upon prolonged incubation, and strong delayed cytotoxicity against tumor cells.

HnRNPA0 promotes MYB expression by interacting with enhancer lncRNA MY34UE-AS in human leukemia cells

MYB is a key regulator of hematopoiesis and erythropoiesis, and dysregulation of MYB is closely involved in the development of leukemia, however the mechanism of MYB regulation remains still unclear so far. Our previous study identified a long noncoding RNA (lncRNA) derived from the −34 kb enhancer of the MYB locus, which can promote MYB expression, the proliferation and migration of human leukemia cells, and is therefore termed MY34UE-AS. Then the interacting partner proteins of MY34UE-AS were identified and studied in the present study. hnRNPA0 was identified as a binding partner of MY34UE-AS through RNA pulldown assay, which was further validated through RNA immunoprecipitation (RIP). hnRNPA0 interacted with MY34UE-AS mainly through its RRM2 domain. hnRNPA0 overexpression upregulated MYB and increased the proliferation and migration of K562 cells, whereas hnRNPA0 knockdown showed opposite effects. Rescue experiments showed MY34UE-AS was required for above mentioned functions of hnRNPA0. These results reveal that hnRNPA0 is involved in leukemia through upregulating MYB expression by interacting with MY34UE-AS, suggesting that the hnRNPA0/MY34UE-AS axis could serve as a potential target for leukemia treatment.

The Potential Effects and Mechanisms of Rhododendron molle Against Rheumatoid Arthritis Based on Network Pharmacology and Molecular Docking

Background: Rheumatoid arthritis (RA) is a self-inflammatory disease with increasing global morbidity and high disability. The Chinese herbal medicine Rhododendron molle G. Dons has been conventionally used to control RA without side effects for hundreds of years, but its effect and mechanism for anti-RA are still unclear. Objective: The objective of this study is to study the potential effect and mechanism of R. molle against RA from the perspective of action targets and molecular pathways. Methods: In this study, systemic network pharmacology was used to explore the potential effect and mechanisms of R. molle against RA, including drug active components collection, target prediction, PPI network construction, and GO and KEGG pathway enrichment analyses. At last, molecular docking was carried out to estimate the pharmacological effects and mechanisms. Results: A total of 19 drug-active compounds from R. molle and 188 potential therapeutic targets for RA were screened. According to the results of molecular docking, the interaction between 4 key active compounds (rhodojaponin VI, quercetin, kaempferol, rhodojaponin VI) and 10 core target proteins (TNF, AKT1, ALB, IL-1β, TP53, EGFR, CASP3, MMP9, PTGS2, BCL2) is the closest. The results of enrichment analysis showed that the most enriched pathways were pathways related to inflammation, human T-cell leukemia virus type I infection, PI3K-Akt and IL-17. Conclusion: The Chinese herbal medicine R. molle may regulate multiple pathways by interacting with multiple drug-active compounds and core targets, and cause the patient's immune system to respond accordingly, reducing the release of inflammatory factors, and relieving joint pain.

In silico predicted compound targeting the IQGAP1-GRD domain selectively inhibits growth of human acute myeloid leukemia

Acute myeloid leukemia (AML) is fatal in the majority of adults. Identification of new therapeutic targets and their pharmacologic modulators are needed to improve outcomes. Previous studies had shown that immunization of rabbits with normal peripheral WBCs that had been incubated with fluorodinitrobenzene elicited high titer antibodies that bound to a spectrum of human leukemias. We report that proteomic analyses of immunoaffinity-purified lysates of primary AML cells showed enrichment of scaffolding protein IQGAP1. Immunohistochemistry and gene-expression analyses confirmed IQGAP1 mRNA overexpression in various cytogenetic subtypes of primary human AML compared to normal hematopoietic cells. shRNA knockdown of IQGAP1 blocked proliferation and clonogenicity of human leukemia cell-lines. To develop small molecules targeting IQGAP1 we performed in-silico screening of 212,966 compounds, selected 4 hits targeting the IQGAP1-GRD domain, and conducted SAR of the ‘fittest hit’ to identify UR778Br, a prototypical agent targeting IQGAP1. UR778Br inhibited proliferation, induced apoptosis, resulted in G2/M arrest, and inhibited colony formation by leukemia cell-lines and primary-AML while sparing normal marrow cells. UR778Br exhibited favorable ADME/T profiles and drug-likeness to treat AML. In summary, AML shows response to IQGAP1 inhibition, and UR778Br, identified through in-silico studies, selectively targeted AML cells while sparing normal marrow.

The tumor suppressor Fat1 is dispensable for normal murine hematopoiesis.

Loss and overexpression of FAT1 occurs among different cancers, with these divergent states equated with tumor suppressor and oncogene activity, respectively. Regarding the latter, FAT1 is highly expressed in a high proportion of human acute leukemias relative to normal blood cells, with evidence pointing to an oncogenic role. We hypothesized that this occurrence represents legacy expression of FAT1 in undefined hematopoietic precursor subsets (i.e. sustained following transformation), predicating a role for FAT1 during normal hematopoiesis. We explored this concept by using the Vav-iCre strain to construct conditional knockout mice in which Fat1 expression was deleted at the hematopoietic stem cell stage. Extensive analysis of precursor and mature blood populations using multipanel flow cytometry revealed no ostensible differences between Fat1 conditional knockout mice and normal littermates. Further functional comparisons involving colony-forming unit and competitive bone marrow transplantation assays support the conclusion that Fat1 is dispensable for normal murine hematopoiesis.

The DNA Methyltransferase Inhibitor 5-Aza-4'-thio-2'-Deoxycytidine Induces C>G Transversions and Acute Lymphoid Leukemia Development.

DNA methyltransferase inhibitors (DNMTi), most commonly cytidine analogs, are compounds that decrease 5'-cytosine methylation. DNMTi are used clinically based on the hypothesis that cytosine demethylation will lead to re-expression of tumor suppressor genes. 5-Aza-4'-thio-2'-deoxycytidine (Aza-TdCyd or ATC) is a recently described thiol-substituted DNMTi that has been shown to have anti-tumor activity in solid tumor models. In this study, we investigated the therapeutic potential of ATC in a murine transplantation model of myelodysplastic syndrome. ATC treatment led to the transformation of transplanted wild-type bone marrow nucleated cells into lymphoid leukemia, and healthy mice treated with ATC also developed lymphoid leukemia. Whole-exome sequencing revealed 1,000 acquired mutations, almost all of which were C>G transversions in a specific 5'-NCG-3' context. These mutations involved dozens of genes involved in human lymphoid leukemia, such as Notch1, Pten, Pax5, Trp53, and Nf1. Human cells treated in vitro with ATC showed 1,000 acquired C>G transversions in a similar context. Deletion of Dck, the rate-limiting enzyme for the cytidine salvage pathway, eliminated C>G transversions. Taken together, these findings demonstrate a highly penetrant mutagenic and leukemogenic phenotype associated with ATC. Significance: Treatment with a DNA methyltransferase inhibitor generates a distinct mutation signature and triggers leukemic transformation, which has important implications for the research and clinical applications of these inhibitors.

Facile Synthesis of a Crystalline Zinc Sulfide/Chitosan Biopolymer Nanocomposite: Characterization and Application for Photocatalytic Degradation of Textile Dyes and Anticancer Activity.

In the present study, we have synthesized a zinc sulfide/chitosan (ZS/CS) nanocomposite by utilizing simple, economical, and environmentally friendly methods. The synthesized nanomaterials were characterized by different analytical techniques such as XRD, FE-SEM, EDS, and FTIR to determine the phase structure, morphology, and elemental composition. FTIR spectroscopy was used to confirm the functional groups of the synthesized zinc sulfide (ZS) nanoparticles and ZS/CS composite. Besides, the optical properties of the as-synthesized nanocomposite was analyzed by a UV-visible spectrophotometer, and the estimated band gap energy is ∼3.03 eV. The photocatalytic efficiency of the synthesized ZS/CS nanocomposite was investigated against two textile dyes, Crystal Violet (CV) and Acid Red-I (AR-I), under UV-visible light irradiation. The nanocomposite showed excellent photocatalytic activity against the dyes, and photodegradation was estimated to be about 93.44 and 90.67% for CV and AR-I, respectively. The nanocomposite was reused for three consecutive cycles. The results revealed that the photocatalyst displayed good reusability during the photocatalytic decomposition and thus is considered a cost-effective and promising photocatalyst in degrading dye pollutants. The kinetic study proved that the pseudo-first-order reaction kinetics was followed by the degradation process. We also examined the anticancer activity of ZS and ZS/CS against human breast and myelogenous leukemia cancer cell lines, namely, MCF-7 and K-562, and the half minimal inhibitory concentrations were found to be less than 50 μg/mL.

Flow cytometric profiles with CD7 and CADM1 in CD4+ T cells are promising indicators for prognosis of aggressive ATL

AbstractAdult T-cell leukemia/lymphoma (ATL) is a poor prognosis hematological malignancy originating from human T-cell leukemia virus 1 (HTLV-1)–infected CD4+ T cells. Flow cytometric plots of CADM1 and CD7 in CD4+ T cells are useful for separating HTLV-1–uninfected T cells and ATL cells. They are indicators of clonal evolution of HTLV-1–infected cells and disease progression of asymptomatic carriers or indolent ATL. However, the impacts of the plots on the clinical course or prognosis of ATL, especially in aggressive ATL, remain unclear. We focused on the N fraction (CD4+ CADM1+ CD7–) reflecting ATL cells and analyzed the flow cytometric profiles and clinical course of 497 samples from 92 HTLV-1–infected patients who were mainly aggressive ATL. The parameters based on N fractions showed significant correlations with known indicators of ATL disease status (soluble interleukin-2 receptor, lactate dehydrogenase, abnormal lymphocytes, etc.) and sensitively reflected the treatment response of aggressive ATL. The parameters based on N fractions significantly stratified the prognosis of aggressive ATL at 4 different time points: before treatment, after 1 course of chemotherapy, at the best response after chemotherapy, and before allogeneic hematopoietic cell transplantation. Even after mogamulizumab administration, which shows potent effects for peripheral blood lesions, the N fraction was still a useful indicator for prognostic estimation. In summary, this report shows that CADM1 vs CD7 plots in CD4+ T cells are useful indicators of the clinical course and prognosis of aggressive ATL. Therefore, this CADM1 and CD7 profile is suggested to be a useful prognostic indicator consistently from HTLV-1 carriers to aggressive ATL.