Myeloid Leukemia Research Articles

Biological Potential and Therapeutic Effectiveness of Hinokiflavone in Medicine: The Effective Components of Herbal Medicines for Treatment of Cancers and Associated Complications

Background: Plants have been providing us medicines and food material for centuries. Traditional system of medicine, including Ayurveda, and Traditional Chinese medicines have been playing important role in health sectors for the treatment of human disorders since very early age. Plant secondary metabolites, including flavonoids, coumarins, saponins, and tannins have significant therapeutic potential in medicine. Biflavonoids are dimers of flavonoids, linked by a C–O–C or C–C bond. Hinokiflavone is an important class of biflavonoids found to be present in Toxicodendron succedaneum, Isophysis tasmanica, Juniperus rigida, Juniperus phoenicea, Platycladi cacumen, Rhus succedanea, Selaginella tamariscina, Platycladus orientalis, Selaginella bryopteris, and Metasequoia glyptostroboides. Methods: Biological potential of hinokiflavone in medicine have been analyzed in the present work through scientific data analysis of various literature work. Scientific database, including Google, Scopus, Science Direct, and PubMed were searched to collect all the scientific information of the present work using terms flavonoid, biflavonoid, herbal medicine, and hinokiflavone. Pharmacological activities of hinokiflavone were analyzed in the present work in very detailed manner. Analytical data of hinokiflavone were collected and analyzed in present work in order to know the biological source of hinokiflavone. Results: Present work signified the biological importance of hinokiflavone against various types of cancerous disorders, including breast cancer, colorectal cancer, esophageal squamous cancer, adenocarcinoma, hepatocellular carcinoma, myeloid leukemia, and melanoma. Further, its antiinflammatory, hepatoprotective, anti-viral, and anti-oxidant potential were also discussed in the present work. Moreover, its biological potential against COVID-19 and hair loss, and procoagulant activity were also summarized in this paper. Analytical data on hinokiflavone signified the importance of various analytical techniques in the extraction, separation, and identification of hinokiflavone with their pharmacokinetic parameters. Conclusion: Present work signified the biological importance and therapeutic potential of hinokiflavone in medicine.

An Expedition on Synthetic Methodology of FDA-approved Anticancer Drugs (2018-2021).

New drugs being established in the market every year produce specified structures for selective biological targeting. With medicinal insights into molecular recognition, these begot molecules open new rooms for designing potential new drug molecules. In this review, we report the compilation and analysis of a total of 56 drugs including 33 organic small molecules (Mobocertinib, Infigratinib, Sotorasib, Trilaciclib, Umbralisib, Tepotinib, Relugolix, Pralsetinib, Decitabine, Ripretinib, Selpercatinib, Capmatinib, Pemigatinib, Tucatinib, Selumetinib, Tazemetostat, Avapritinib, Zanubrutinib, Entrectinib, Pexidartinib, Darolutamide, Selinexor, Alpelisib, Erdafitinib, Gilteritinib, Larotrectinib, Glasdegib, Lorlatinib, Talazoparib, Dacomitinib, Duvelisib, Ivosidenib, Apalutamide), 6 metal complexes (Edotreotide Gallium Ga-68, fluoroestradiol F-18, Cu 64 dotatate, Gallium 68 PSMA-11, Piflufolastat F-18, 177Lu (lutetium)), 16 macromolecules as monoclonal antibody conjugates (Brentuximabvedotin, Amivantamab-vmjw, Loncastuximabtesirine, Dostarlimab, Margetuximab, Naxitamab, Belantamabmafodotin, Tafasitamab, Inebilizumab, SacituzumabGovitecan, Isatuximab, Trastuzumab, Enfortumabvedotin, Polatuzumab, Cemiplimab, Mogamulizumab) and 1 peptide enzyme (Erwiniachrysanthemi-derived asparaginase) approved by the U.S. FDA between 2018 to 2021. These drugs act as anticancer agents against various cancer types, especially non-small cell lung, lymphoma, breast, prostate, multiple myeloma, neuroendocrine tumor, cervical, bladder, cholangiocarcinoma, myeloid leukemia, gastrointestinal, neuroblastoma, thyroid, epithelioid and cutaneous squamous cell carcinoma. The review comprises the key structural features, approval times, target selectivity, mechanisms of action, therapeutic indication, formulations, and possible synthetic approaches of these approved drugs. These crucial details will benefit the scientific community for futuristic new developments in this arena.

JAK2 as Predictor of Therapeutic Response in Patients with Chronic Myeloid Leukemia Treated with Imatinib

Background. Chronic myeloid leukemia (CML) or chronic granulocytic leukemia is a myeloproliferative neoplasm indicated by the presence of the Philadelphia (Ph+) chromosome. First-line tyrosine kinase inhibitor, imatinib, is the gold standard for treatment. However, there has been known unresponsiveness to treatment, especially due to the involvement of other genes, such as the Janus kinase 2 (JAK2) gene. This study aimed to evaluate the relationships between JAK2 levels and complete hematological response (CHR), as well as early molecular response (EMR) after 3 months of imatinib treatment in patients with chronic phase CML. Methods. Patients with Ph+ CML in the chronic phase (n = 40; mean age, 40 ± 11 years) were recruited to complete assessments consisting of clinical examination and blood test, including evaluation of complete blood counts and the JAK2 levels, at baseline and following 3 months of therapy with imatinib (at an oral dose of 400 mg per day). Subjects were divided into two groups according to the presence of CHR and EMR. Results. JAK2 gene levels, phosphorylated, and total JAK2 proteins at baseline were significantly lower in the group with the presence of CHR and EMR. In addition, baseline JAK2 levels, including JAK2 gene expression, phosphorylated, and total JAK2 proteins, were negatively correlated with the presence of CHR and EMR. Conclusions. Based on these findings, JAK2 levels may be a potential indicator for evaluating treatment response on imatinib due to its role in the pathophysiology of CML.

Comparison of the 2022 world health organization classification and international consensus classification in myelodysplastic syndromes/neoplasms

In 2022, two novel classification systems for myelodysplastic syndromes/neoplasms (MDS) have been proposed: the International Consensus Classification (ICC) and the 2022 World Health Organization (WHO-2022) classification. These two contemporary systems exhibit numerous shared features but also diverge significantly in terminology and the definition of new entities. Thus, we retrospectively validated the ICC and WHO-2022 classification and found that both systems promoted efficient segregation of this heterogeneous disease. After examining the distinction between the two systems, we showed that a peripheral blood blast percentage ≥ 5% indicates adverse survival. Identifying MDS/acute myeloid leukemia with MDS-related gene mutations or cytogenetic abnormalities helps differentiate survival outcomes. In MDS, not otherwise specified patients, those diagnosed with hypoplastic MDS and single lineage dysplasia displayed a trend of superior survival compared to other low-risk MDS patients. Furthermore, the impact of bone marrow fibrosis on survival was less pronounced within the ICC framework. Allogeneic transplantation appears to improve outcomes for patients diagnosed with MDS with excess blasts in the ICC. Therefore, we proposed an integrated system that may lead to the accurate diagnosis and advancement of future research for MDS. Prospective studies are warranted to validate this refined classification.

Abstract LB068: Repurposing chimeric antigen receptor regulatory T cells for treating cancer

Abstract Solid tumors are the deadliest form of cancer. Over the past decade, chimeric antigen receptor (CAR) T-cell therapy has led to remarkable regression rates in leukemia and lymphoma. However, solid tumors have remained refractory to CAR T-cell therapy, with CAR T cells either failing to penetrate the solid tumor microenvironment (TME) or becoming exhausted once in it. Mechanisms behind these properties of the TME include nutrient scarcity, aberrant vascularization, stromal cell deposition, expression of inhibitory immune receptors by cancer cells, and the presence of immunosuppressive cells. Interestingly, there is a subset of T cells found in the TME - regulatory T cells (Tregs). Dedicated to suppressing immune responses, Tregs constitute a barrier to anticancer immunity by migrating to and heavily accumulating in solid tumors, inhibiting local immunity. Tregs can be redirected towards any cell surface antigen using a CAR and have been shown to be cytotoxic towards target antigen presenting cells. Can Tregs be converted from tumor protectors to anti-tumor effector cells? To test the anti-tumor potential of CAR Tregs, we modified human Tregs with an anti-CD19 CD28-CD3z CAR. Tregs activated via the CAR or endogenous TCR/CD28 were evaluated at the functional and gene expression levels. CAR and endogenous TCR/CD28 activation resulted in similar cell expansion and Treg stability (FOXP3 and HELIOS expression). However, CAR-mediated activation markedly increased Treg proinflammatory cytokine production. Moreover, compared to their TCR/CD28-activated counterparts, CAR Tregs displayed increased cytotoxic activity towards tumor cells and a diminished capacity to modulate antigen-presenting cells and suppress T cell proliferation, suggesting a global shift from suppression to inflammation. Strikingly, CAR Tregs suppressed tumor growth in immunodeficient mice inoculated with antigen-expressing B-cell leukemia, myeloid leukemia, and lung epithelial carcinoma. Single-cell RNA sequencing identified a cell cluster enriched in CAR Tregs characterized by high expression of effector T cell genes, such as IFNG, GZMB, and CD40LG, revealing that CAR activation creates a highly active population of proinflammatory Tregs. Multiplex cytokine analysis, whole-transcriptome RNA-seq, and intracellular cytokine staining confirmed that IFNG production by FOXP3+ Tregs is induced specifically by CAR activation. Of note, murine CAR Tregs are also cytotoxic towards tumor cells. Current experiments are focused on pinpointing and validating transcription factors and surface markers characteristic of proinflammatory CAR Tregs and further assessing CAR Treg antitumor efficacy in vivo. In conclusion, CAR-mediated activation induces a novel proinflammatory Treg phenotype that can be exploited in the next generation of engineered immune cell therapies against solid tumors. Citation Format: Leonardo M. Ferreira, Russell W. Cochrane, Rob A. Robino, Bryan Granger, Eva Allen, Vishnu Gudivada, Aguirre A. de Cubas, Stefano Berto. Repurposing chimeric antigen receptor regulatory T cells for treating cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB068.

A novel fluorescent probe based imprinted polymer-coated magnetite for the detection of imatinib leukemia anti-cancer drug traces in human plasma samples

Myeloid leukemia is a chronic cancer, which associated with abnormal BCR-ABL tyrosine kinase activity. Imatinib (IMB) acts as a tyrosine kinase inhibitor and averts tumor growth in cancer cells by controlling cell division, so it is urgent to develop an effective assay to detect and monitor its IMB concentration. Therefore, an innovative fluorescent biomimetic sensor is a promising sensing material that constructed for the efficient recognition of IMB and displays excellent selectivity and sensitivity stemming from molecularly imprinted polymer@Fe3O4 (MIP@Fe3O4). The detection strategy depends on the recognition of IMB molecules at the imprinted sites in the presence of coexisting molecules, which are then transferred to the fluorescence signal. The synthesized MIP@Fe3O4 was characterized using Fourier-transform infrared spectroscopy (FT-IR), scanning electron microscopy (SEM), and atomic force microscopy (AFM). Furthermore, computational studies of the band gap (EHOMO-ELUMO) of the monomers, IMB, and their complexes were performed. These results confirmed that the copolymer is the most appropriate and has high stability (Binding energy; 0.004 x 10-19 KJ) and low reactivity. A comprehensive linear response over IMB concentrations from 5 × 10-6 mol/L to 8 × 10-4 mol/L with a low detection limit of 9.3 × 10-7 mol/L was achieved. Furthermore, the proposed technique displayed long-term stability (over 2 months), high intermediate precision (RSD<2.1 %), good reproducibility (RSD <1.9 %), and outstanding selectivity toward IMB over analogous molecules with similar chemical and spatial structure (no interference by 100 to 150-fold of the competitors). Owing to these merits, the proposed fluorescence sensor was utilized to detect IMB in drug tablets and human plasma, and satisfactory results (99.3–100.4 %) were obtained. Thus, the synthesized fluorescence sensor is a promising platform for IMB sensing in various applications.

Triangulation of epidemiological evidence and risk of bias evaluation: A proposed framework and applied example using formaldehyde exposure and risk of myeloid leukemias

Evidence triangulation may help identify the impact of study design elements on study findings and to tease out biased results when evaluating potential causal relationships; however, methods for triangulating epidemiologic evidence are evolving and have not been standardized. Building upon key principles of epidemiologic evidence triangulation and risk of bias assessment, and responding to the National Academies of Sciences, Engineering, and Medicine (NASEM) call for applied triangulation examples, the objective of this manuscript is to propose a triangulation framework and to apply it as an illustrative example to epidemiologic studies examining the possible relationship between occupational formaldehyde exposure and risk of myeloid leukemias (ML) including acute (AML) and chronic (CML) types.A nine-component triangulation framework for epidemiological evidence was developed incorporating study quality and ROB guidance from various federal health agencies (i.e., US EPA TSCA and NTP OHAT). Several components of the triangulation framework also drew from widely used epidemiological analytic tools such as stratified meta-analysis and sensitivity analysis. Regarding the applied example, fourteen studies were identified and assessed using the following primary study quality domains to explore potential key sources of bias: 1) study design and analysis; 2) study participation; 3) exposure assessment; 4) outcome assessment; and 5) potential confounding. Across studies, methodological limitations possibly contributing to biased results were observed within most domains. Interestingly, results from one study – often providing the largest and least-precise relative risk estimates, likely reflecting study biases, deviated from most primary study findings indicating no such associations. Triangulation of epidemiological evidence appears to be helpful in exploring inconsistent results for the identification of study results possibly reflecting various biases. Nonetheless, triangulation methodologies require additional development and application to real-world examples to enhance objectivity and reproducibility.

15 years Ludwig Boltzmann Institute for Hematology and Oncology (LBI HO): achievements and future perspectives

SummaryCancer stem cells, also known as leukemic stem cells (LSC) in the context of leukemias, are an emerging topic in translational oncology and hematology. The Ludwig Boltzmann Institute for Hematology and Oncology (LBI HO) was established in 2008 with the aim to translate LSC concepts into clinical practice. Major specific aims of the LBI HO are to identify LSC in various blood cell disorders and to improve anti-leukemic therapies by establishing LSC-targeting and LSC-eradicating approaches with the ultimate aim to translate these concepts into clinical practice. In addition, the LBI HO identified a number of diagnostic and prognostic LSC markers in various blood cell malignancies. Members of the LBI HO have also developed precision medicine tools and personalized medicine approaches around LSC in applied hematology. As a result, diagnosis, prognostication and therapy have improved in the past 10 years. Major disease models are myeloid leukemias and mast cell neoplasms. Finally, the LBI HO consortium launched several projects in the field of open innovation in science where patient-derived initiatives and their input supported the scientific community. Key aims for the future of the LBI HO are to develop LSC-related concepts and strategies further, with the long-term vision to cure more patients with hematologic malignancies.

Cytotoxicity of quercetin and curcumin combination against HeLa cells line

Curcumin and quercetin combination are potential candidates for anticancer. Previous studies reported this combination active against several cancer cells including breast cancer, myeloid leukemia, and melanoma. However, the activity of this combination against cervical cancer has not been reported, yet. This study aimed to evaluate the cytotoxicity of the combination of curcumin and quercetin against HeLa and Vero cells. MTT assay was applied to evaluate cell growth inhibition. The inhibitory 50% concentration (IC50) of curcumin and quercetin on HeLa and Vero cells was determined and the selectivity index (SI) was then calculated. Combination index (CI) was calculated after evaluation of the cytotoxicity of the curcumin and quercetin combination at various concentration of 1 IC50, ½ IC50, and ¼ IC50. The IC50 of the curcumin against the HeLa and Vero cells were 26.57 ± 2.00 μM and 73.89 ± 12.93 μM with a SI of 2.78. Whereas the IC50 of the quercetin against the HeLa and Vero cells were 149.52 ± 21.09 μM and 1094.47 ± 15.68 μM with a SI of 7.32. The CI of combinations of curcumin and quercetin at concentrations of ¼ IC50 was 0.78 indicating a mild-moderate synergistic effect, whereas the combination at a concentration of 1 IC50 or ½ IC50, the CI value was &gt;0.9 indicating an antagonistic effect.

Acquired immune resistance is associated with interferon signature and modulation of KLF6/c-MYB transcription factors in myeloid leukemia.

Resistance to immunity is associated with the selection of cancer cells with superior capacities to survive inflammatory reactions. Here, we tailored an ex vivo immune selection model for acute myeloid leukemia (AML) and isolated the residual subpopulations as "immune-experienced" AML (ieAML) cells. We confirmed that upon surviving the immune reactions, the malignant blasts frequently decelerated proliferation, displayed features of myeloid differentiation and activation, and lost immunogenicity. Transcriptomic analyses revealed a limited number of commonly altered pathways and differentially expressed genes in all ieAML cells derived from distinct parental cell lines. Molecular signatures predominantly associated with interferon and inflammatory cytokine signaling were enriched in the AML cells resisting the T-cell-mediated immune reactions. Moreover, the expression and nuclear localization of the transcription factors c-MYB and KLF6 were noted as the putative markers for immune resistance and identified in subpopulations of AML blasts in the patients' bone marrow aspirates. The immune modulatory capacities of ieAML cells lasted for a restricted period when the immune selection pressure was omitted. In conclusion, myeloid leukemia cells harbor subpopulations that can adapt to the harsh conditions established by immune reactions, and a previous "immune experience" is marked with IFN signature and may pave the way for susceptibility to immune intervention therapies.

Identification, Isolation, and Charecterisation of a Novel Degradation Impurity of Busulfan Using Preparative Chromatography, NMR and LC-MS.

Busulfan is the most effective medication for treating chronic myelogenous or granulocytic leukemia because it has cytotoxic properties that harm or kill hematopoietic cells. It cannot absorb light in the ultraviolet range due to its structure. Because of this, it is very challenging to quantify using traditional HPLC coupled with UV/PDA detectors. So, using sodium diethyldithiocarbamate, a derivatization method was developed to quantify related impurities. A significant unknown impurity was identified in derivatized samples of busulfan with a noticeably high percentage level was discovered during routine drug testing. Isolation, and characterisation of the unknown impurity observed in the samples and to identify the root-cause. Preparative HPLC was used to isolate the unidentified derivatized impurity, and 1H NMR, 13C NMR, and MS were used to decipher its structural components. The spectral characterisation data analysis shows that the unknown impurity is related to Busulfan. Additionally, it is noted that the impurity is developing as a result of the residual buffer used to prepare the derivatizing reagent. The isolated impurity was found to be comparable to that found in busulfan drug substances, according to the results of the characterisation tools. An alternative method of reagent preparation is optimized and deemed satisfactory because the buffer used in reagent preparation is the only factor contributing to the formation of impurities. Using cutting-edge analytical characterisation tools, it was possible to explain the structural characteristics of an unknown impurity and discover that it is a novel impurity, which undoubtedly contributed to the comprehension of understanding of drug substance reaction properties.

Insights into the Molecular Mechanisms of Genetic Predisposition to Hematopoietic Malignancies: The Importance of Gene-Environment Interactions.

The recognition of host genetic factors underlying susceptibility to hematopoietic malignancies has increased greatly over the last decade. Historically, germline predisposition was thought to primarily affect the young. However, emerging data indicate that hematopoietic malignancies that develop in people of all ages across the human lifespan can derive from germline predisposing conditions and are not exclusively observed in younger individuals. The age at which hematopoietic malignancies manifest appears to correlate with distinct underlying biological pathways. Progression from having a deleterious germline variant to being diagnosed with overt malignancy involves complex, multistep gene-environment interactions with key external triggers, such as infection and inflammatory stimuli, driving clonal progression. Understanding the mechanisms by which predisposed clones transform under specific pressures may reveal strategies to better treat and even prevent hematopoietic malignancies from occurring.Recent unbiased genome-wide sequencing studies of children and adults with hematopoietic malignancies have revealed novel genes in which disease-causing variants are of germline origin. This paradigm shift is spearheaded by findings in myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) as well as acute lymphoblastic leukemia, but it also encompasses other cancer types. Although not without challenges, the field of genetic cancer predisposition is advancing quickly, and a better understanding of the genetic basis of hematopoietic malignancies risk affects therapeutic decisions as well as genetic counseling and testing of at-risk family members.

CLCN3 in mediating the proliferation of human ovarian cancer cells.

Chloride channel-3 (CLCN3), a crucial component of the voltage-gated chloride channel family, is implicated in numerous physiological and pathophysiological processes. This study aimed to investigate the characteristics of CLCN3 in pancancer and its influence on the immune response through the use of a range of databases. Concurrently, we assessed the impact of CLCN3 on the proliferation of ovarian cancer (OC) cells and explored its potential mechanisms. We employed the Tumor Immune Estimation Resource (TIMER) 2.0 and Clinical Proteomic Tumor Analysis Consortium (CPTAC) databases to examine the messenger RNA (mRNA) and the protein expression of CLCN3 across various cancers. The prognostic significance of CLCN3 was evaluated using the Gene Expression Profiling Interactive Analysis 2.0 (GEPIA 2.0) database. The University of Alabama at Birmingham Cancer Data Analysis Portal (UALCAN) facilitated the analysis of CLCN3 promoter methylation levels. The association between CLCN3 expression and tumor-infiltrating immune cells was investigated using various algorithms. The cBioportal database facilitated the analysis of CLCN3 mutations and mutation sites across various cancers. The Tumor-Immune System Interactions Database (TISIDB) database was employed to explore the correlation between CLCN3 expression and immune or molecular subtypes across a variety of cancer types. We collected ovarian tissue samples, encompassing both normal ovarian and OC tissues. The human OC cell lines, SKOV3 cells and OVCAR433 cells, were cultured. CLCN3 expression was determined via reverse-transcription quantitative polymerase chain reaction (RT-qPCR), while phosphatidylinositol 3-kinase/Akt kinase (PI3K/AKT) expression was detected using Western blot. We utilized small interfering RNA (siRNA) technology to suppress CLCN3 expression. The proliferative capacity of SKOV3 and OVCAR433 cells was assessed using the Cell Counting Kit 8 (CCK-8) assay. CLCN3 demonstrated an aberrant expression in a number of cancer types and was markedly reduced in OC tissues. Poor prognosis in cervical squamous cell cancer and myeloid leukemia was linked to excessive expression of CLCN3. The examination of immune cell infiltration, which included CD8+ T cells, B cells, T regulatory cells, and cancer-associated fibroblast cells, showed a strong association with aberrant CLCN3 expression. Following the use of siRNA technology, the ability of the ovarian carcinoma cell line SKOV3 and OVCAR433 to proliferate as well as the expression of PI3K/AKT both increased. CLCN3 is a possible biomarker for immune-related processes and the prognosis of cancer, and the PI3K/AKT signaling pathway may affect OC cells' ability to proliferate.

Epidemiology of childhood acute leukemias in marginalized populations of the central-south region of Mexico: results from a population-based registry.

Acute leukemias (AL) are the main types of cancer in children worldwide. In Mexico, they represent one of the main causes of death in children under 20 years of age. Most of the studies on the incidence of AL in Mexico have been developed in the urban context of Greater Mexico City and no previous studies have been conducted in the central-south of the country through a population-based study. The aim of the present work was to identify the general and specific incidence rates of pediatric AL in three states of the south-central region of Mexico considered as some of the marginalized populations of Mexico (Puebla, Tlaxcala, and Oaxaca). A population-based study was conducted. Children aged less than 20 years, resident in these states, and newly diagnosed with AL in public/private hospitals during the period 2021-2022 were identified. Crude incidence rates (cIR), standardized incidence rates (ASIRw), and incidence rates by state subregions (ASIRsr) were calculated. Rates were calculated using the direct and indirect method and reported per million children under 20 years of age. In addition, specific rates were calculated by age group, sex, leukemia subtype, and immunophenotype. A total of 388 cases with AL were registered. In the three states, the ASIRw for AL was 51.5 cases per million (0-14 years); in Puebla, it was 53.2, Tlaxcala 54.7, and Oaxaca de 47.7. In the age group between 0-19 years, the ASIRw were 44.3, 46.4, 48.2, and 49.6, in Puebla, Tlaxcala, and Oaxaca, respectively. B-cell acute lymphoblastic leukemia was the most common subtype across the three states. The incidence of childhood AL in the central-south region of Mexico is within the range of rates reported in other populations of Latin American origin. Two incidence peaks were identified for lymphoblastic and myeloid leukemias. In addition, differences in the incidence of the disease were observed among state subregions which could be attributed to social factors linked to the ethnic origin of the inhabitants. Nonetheless, this hypothesis requires further investigation.

Zinc as a potential regulator of the BCR-ABL oncogene in chronic myelocytic leukemia cells

BackgroundGenerally, decreased zinc in the serum of tumor patients but increased zinc in tumor cells can be observed. However, the role of zinc homeostasis in myeloid leukemia remains elusive. BCR-ABL is essential for the initiation, maintenance, and progression of chronic myelocytic leukemia (CML). We are currently investigating the association between zinc homeostasis and CML. MethodsGenes involved in zinc homeostasis were examined using three GEO datasets. Western blotting and qPCR were used to investigate the effects of zinc depletion on BCR-ABL expression. Furthermore, the effect of TPEN on BCR-ABL promoter activity was determined using the dual-luciferase reporter assay. MRNA stability and protein stability of BCR-ABL were assessed using actinomycin D and cycloheximide. ResultsTranscriptome data mining revealed that zinc homeostasis-related genes were associated with CML progression and drug resistance. Several zinc homeostasis genes were affected by TPEN. Additionally, we found that zinc depletion by TPEN decreased BCR-ABL mRNA stability and transcriptional activity in K562 CML cells. Zinc supplementation and sodium nitroprusside treatment reversed BCR-ABL downregulation by TPEN, suggesting zinc- and nitric oxide-dependent mechanisms. ConclusionOur in vitro findings may help to understand the role of zinc homeostasis in BCR-ABL regulation and thus highlight the importance of zinc homeostasis in CML.

Clinical Outcomes of TP53 Mutated Myelodysplastic Syndrome/Acute Myeloid Leukemia; A Single Center Experience

Clinical Outcomes of TP53 Mutated Myelodysplastic Syndrome/Acute Myeloid Leukemia; A Single Center Experience

Enhancing Early Detection of Blood Disorders through A Novel Hybrid Modeling Approach

Blood disorders are such conditions that impact the blood’s ability to function correctly. There is a range of different symptoms depending on the type. There are several different types of blood disorders such as Leukemia, chronic myelocytic leukemia, lymphoma, myelofibrosis, polycythemia, thrombocytopenia, anemia, and leukocytosis. Some resolve completely with therapy or do not cause symptoms and do not affect overall lifespan. Some are chronic and lifelong but do not affect how an individual lives. Other blood disorders, like sickle cell disease and blood cancers, can be even fatal. There needs to be a capture of hidden information in the medical data for detecting diseases in the early stages. This paper presents a novel hybrid modeling strategy that makes use of the synergy between two methods with histogram-based gradient boosting classifier tree and random subspace. It should be emphasized that the combination of these two models is being employed in this study for the first time. We present this novel model built for the assessment of blood diseases. The results show that the proposed model can predict the tumor of blood disease better than the other classifiers.

Pediatric glioma histone H3.3 K27M/G34R mutations drive abnormalities in PML nuclear bodies

BackgroundPoint mutations in histone variant H3.3 (H3.3K27M, H3.3G34R) and the H3.3-specific ATRX/DAXX chaperone complex are frequent events in pediatric gliomas. These H3.3 point mutations affect many chromatin modifications but the exact oncogenic mechanisms are currently unclear. Histone H3.3 is known to localize to nuclear compartments known as promyelocytic leukemia (PML) nuclear bodies, which are frequently mutated and confirmed as oncogenic drivers in acute promyelocytic leukemia.ResultsWe find that the pediatric glioma-associated H3.3 point mutations disrupt the formation of PML nuclear bodies and this prevents differentiation down glial lineages. Similar to leukemias driven by PML mutations, H3.3-mutated glioma cells are sensitive to drugs that target PML bodies. We also find that point mutations in IDH1/2—which are common events in adult gliomas and myeloid leukemias—also disrupt the formation of PML bodies.ConclusionsWe identify PML as a contributor to oncogenesis in a subset of gliomas and show that targeting PML bodies is effective in treating these H3.3-mutated pediatric gliomas.

Sickle Cell Trait As a Risk Factor for Leukemia: A Nationwide Study

INTRODUCTION: Leukemia is a cancer of blood-forming cells. It can arise from cells of lymphoid or myeloid lineage. It can arise from genetic mutations in tumor suppressor genes, proto-oncogenes or both. It affects over two million people worldwide. A combination of genetic factors and extrinsic factors are believed to play a role. Sickle cell disease (SCD), an inherited disorder leading to the formation of abnormal hemoglobin (HbS) and red blood cell sickling, has been shown to increase the risk for leukemia, presumably due to an increased bone marrow turnover rate. We aimed to explore if sickle cell trait (SCT), when people inherit only one of the two sickle cell genes, is associated with an increased risk for leukemia. METHODS: In this case-control study, we evaluated an association between leukemia (and its subtypes) and SCT in a nationwide cohort of hospitalized patients included in the National Inpatient Sample (NIS) 2016-2019 database. The inclusion criteria for cases were patients who had any of the following ICD-10-CM codes for leukemia: C91 (lymphoid leukemia), C92 (myeloid leukemia), C93 (monocytic leukemia), C94 (other leukemia of specified cell type), and C95 (leukemia of unspecified cell type). The exclusion criteria were Down syndrome (Q90), Fanconi anemia (D61.09), ataxia-telangiectasia (G11.3), Bloom syndrome (Q82), myelodysplastic syndrome (D46), lymphoma (C81, 85), and solid malignancies (C00-75) as these diseases and/or their treatments are known to increase the risk for leukemia independently of SCT (ICD-10-CM D57.3). The controls included patients in the NIS database who do not have the ICD-10-CM codes for leukemia and meet the exclusion criteria applied to the cases. For each year, we used a 1:4 propensity score matching routine. Our match variables were sex, the six race categories used by NIS, and 11 age groups. Four perfect matches (controls) were identified for each case (‘any leukemia’ diagnosis). Patient characteristics were compared using Pearson chi-squared test. Odds ratios (ORs) were calculated for ‘any leukemia’ diagnosis, as well as for each subtype of leukemia. Five multivariate logistic regression models were used to examine the relationship between the leukemia subtypes and SCT while controlling for age group, sex, and race. RESULTS: We identified 181,676 cases and 726,704 controls. The mean age of subjects was 59 years. The majority of subjects (56%) were male. A greater proportion of patients with SCT were found among cases (0.12%) compared to controls (0.08%) (p &amp;lt; 0.0001). The OR for ‘any leukemia’ was 1.48 (95% CI 1.27-1.73, p &amp;lt; 0.0001). When the association between SCT and specific subtypes of leukemia was evaluated, it was statistically significant for myeloid and monocytic leukemias, OR 1.74 (95% CI 1.40 - 2.17) and 2.20 (95% CI 1.09 - 4.42) correspondingly. CONCLUSION: Our case-control study revealed statistically significantly higher odds of SCT among patients with any leukemia (and specifically myeloid and monocytic leukemias) as compared to controls which can be postulated to the common myeloid progenitor lineage of erythrocytes. Our results suggest that, similarly to SCD, SCT although a benign condition can increase the risk for leukemia. To better understand this association, future prospective studies are needed for the mapping of individual risk factors and examining the HbS% levels in SCT carriers who go on to develop leukemia.

Patient Preference Studies in Hematologic Malignancies: A Systematic Review

Background: New therapies have brought about an unprecedented expansion of treatment options for patients with hematologic malignancies that require a greater understanding patient preferences, both to inform treatment decisions and direct further patient-focused drug development. We sought to synthesize existing literature evaluating the preferences of patients with hematologic malignancies to consolidate relevant knowledge and identify future directions for research. Methods: We conducted a systematic review in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines (PROSPERO 2022 CRD42022364647). We searched for articles published in English from PubMed and Embase. Included articles reported primary data on the preferences of patients with hematologic malignancies or patient proxies. Review articles, articles utilizing only secondary data, and abstracts without full text were excluded. Two authors independently reviewed all abstracts and assessed studies for full-text eligibility. Conflicts were resolved by group discussion. Risk of bias (quality) and conflict of interest were assessed. Data extraction included population, method of preference elicitation, attributes included, and relative strength of preferences. Results: A total of 3,520 studies were identified, 2,960 abstracts were screened following removal of duplicates, 239 underwent full-text review, and 74 were included in data extraction. Among the 74 studies, 59 (80%) were published in the last 10 years. In total, 16,986 patients or patient proxies were represented across selected studies. Studies included patients with lymphoma (n=33, 45%), myeloma (n=25, 34%), acute myeloid (n=15, 20%) and lymphoid (n=12, 16%) leukemia, and chronic lymphoid (n=11, 15%) and myeloid leukemia (n=10, 14%). Most studies included patients from Europe (n=30), the United States (n=26), or Canada (n=10). Nearly all (n=70, 95%) included only adults. Most studies were cross-sectional (n=60, 81%), qualitative (n=13, 18%), or mixed-methods (n=13, 18%). Only 1 study was a prospective randomized trial. Preference elicitation methods included study-specific surveys (n=31, 42%), discrete choice experiments (n=28, 38%), and qualitative interviews (n=19, 26%). Most studies elicited patient preferences for treatment outcomes (n=50, 68%) followed by communication (n=14, 19%), and route of administration of therapies (n=7, 9%). Attributes included in treatment outcome studies varied but many included overall/progression free survival (n=30, 60%), side effects (n=28, 56%), route of administration (n=16, 32%), or cost (n=11, 22%). Strength of preference for outcomes was heterogeneous across studies though overall survival was frequently most important to patients. Most studies sought to inform clinical decisions (n=49, 66%), followed by policy (n=13, 18%) and regulatory decision-makers (n=6, 8%). Most studies were of high (n=44, 59%) or moderate (n=26, 35%) quality. Funding for the studies came from pharmaceutical companies (n=25, 34%), government grants (n=20, 27%), and foundations (n=18, 24%). Some studies had apparent (n=16, 22%) or likely (n=9, 12%) conflicts of interest. Only 4 studies (5%) reported implementation outcomes such as acceptability or feasibility. Conclusions: Numerous well-designed studies have been published describing the preferences of patients with hematologic malignancies. Most of these studies were cross-sectional and relied on direct elicitation or discrete choice experiments to elicit preferences. Treatment outcome preferences varied widely across studies and patient populations. This heterogeneity supports the essential role for shared decision-making and individualization of treatment recommendations for each patient. Although many studies sought to generate data to inform clinical decisions, studies evaluating how patient preference data inform individual treatment decisions are largely absent. Future work is needed to support the clinical implementation of preference measures and to standardize relevant attributes for individual diseases and populations.