Proliferation Of Hematopoietic Cells Research Articles

Developments of Fms-like Tyrosine Kinase 3 Inhibitors as Anticancer Agents for AML Treatment.

FMS-like tyrosine kinase 3 (FLT3) is a commonly mutated gene in acute myeloid leukemia. As a receptor tyrosine kinase (RTK), FLT3 plays a role in the proliferation and differentiation of hematopoietic stem cells. As the most frequent molecular alteration in AML, FLT3 has drawn the attention of many researchers, and a lot of small molecule inhibitors targeting FLT3 have been intensively investigated as potential drugs for AML therapy. In this paper, PubMed and SciFinder® were used as a tool; the publications about "FLT3 inhibitor" and "Acute myeloid leukemia" were surveyed from 2014 to the present with an exclusion of those published as patents. In this study, the structural characterization and biological activities of representative FLT3 inhibitors were summarized. The major challenges and future directions for further research are discussed. Recently, numerous FLT3 inhibitors have been discovered and employed in FLT3-mutated AML treatment. In order to overcome the drug resistance caused by FLT3 mutations, screening multitargets FLT3 inhibitors has become the main research direction. In addition, the emergence of irreversible FLT3 inhibitors also provides new ideas for discovering new FLT3 inhibitors.

Effects of PM2.5 exposure on hematopoiesis and coupled immune disorder in adult male mice

Fine particulate matter, namely PM2.5, increases the risk of morbidity and mortality in various systems, including the hematopoietic and immune systems. However, there is limited experimental evidence supporting the association between PM2.5 exposure and hematopoietic outcomes as most studies focus on epidemiological data. In this study, adult male mice were exposed to PM2.5 for a long time to investigate hematopoietic toxicity. There were significant increases in red blood cells (RBC), hemoglobin (HGB), and white blood cells (WBC) in peripheral blood after 5-month real-environmental PM2.5 exposure, indicating elevated circulatory inflammation and potential hematopoietic abnormality. Moreover, we observed abnormal proliferation and differentiation of hematopoietic stem and progenitor cells (HSPCs), along with altered mRNA levels of hematopoietic genes and increased proinflammatory factors in the bone marrow (BM). Transcriptomic analysis of BM cells suggested that PM2.5 exposure activated immune responses associated with lymphocytes. Then, PM2.5 exposure via intratracheal instillation was performed for 8 weeks to verify the toxic effect. The results of the complete blood count were similar to those of real-environmental exposure, with drastic changes in the number and function of HSPCs, as well as mRNA levels of the hematopoietic genes and increased inflammatory factors in the BM being detected. Furthermore, lymphocyte subsets changed significantly in the BM and spleen, confirming immune disorder following PM2.5 exposure. In conclusion, PM2.5 interfered with the process of BM hematopoiesis by triggering inflammation and leading to immune disorder. Our study provided experimental evidence for the hematopoietic toxicity of PM2.5 and highlighted the significance of reducing air pollution.

Mesenchymal Stem Cells in Myelodysplastic Syndromes and Leukaemia.

Mesenchymal stem cells (MSCs) are one of the main residents in the bone marrow (BM) and have an essential role in the regulation of haematopoietic stem cell (HSC) differentiation and proliferation. Myelodysplastic syndromes (MDSs) are a group of myeloid disorders impacting haematopoietic stem and progenitor cells (HSCPs) that are characterised by BM failure, ineffective haematopoiesis, cytopenia, and a high risk of transformation through the expansion of MDS clones together with additional genetic defects. It has been indicated that MSCs play anti-tumorigenic roles such as in cell cycle arrest and pro-tumorigenic roles including the induction of metastasis in MDS and leukaemia. Growing evidence has shown that MSCs have impaired functions in MDS, such as decreased proliferation capacity, differentiation ability, haematopoiesis support, and immunomodulation function and increased inflammatory alterations within the BM through some intracellular pathways such as Notch and Wnt and extracellular modulators abnormally secreted by MSCs, including increased expression of inflammatory factors and decreased expression of haematopoietic factors, contributing to the development and progression of MDSs. Therefore, MSCs can be targeted for the treatment of MDSs and leukaemia. However, it remains unclear what drives MSCs to behave abnormally. In this review, dysregulations in MSCs and their contributions to myeloid haematological malignancies will be discussed.

Integrating network pharmacology and experimental validation to explore the mitophagy-associated pharmacological mechanism of modified Shisiwei Jianzhong decoction against aplastic anemia.

The aim of this work was to investigate the therapeutic effect of modified Shisiwei Jianzhong Decoction (SJD) on aplastic anemia (AA) and its potential pharmacological mechanism from the perspective of mitophagy. A comprehensive approach combining network pharmacology, mendelian randomization, molecular dockingand animal experiments was applied to evaluate the properties of SJD against AA. By integrating multiple databases, it was determined that SJD exerted its therapeutic effect on AA by targeting three key targets [mammalian target of rapamycin (MTOR), poly(ADP-ribose) polymerase 1 (PARP1) and Sirtuin 1 (SIRT1)] through four core compounds (quercetin, resveratrol, genistein and curcumin). Mendelian randomization analysis identified MTOR as a risk factor for AA occurrence while PARP1 was a protective factor. Results of animal experiments showed that SJD improved peripheral blood counts and promoted the proliferation of hematopoietic stem cells. Mechanistically, SJD, especially at high dose, played a therapeutic role in AA by activating mitophagy-related proteins PTEN induced kinase 1 (PINK1)/Parkin and inhibiting the phosphatidylinositol 3-kinase (PI3K)/protein kinase (AKT)/MTOR pathway. This study revealed for the first time the core chemical composition of SJD and its pharmacological effects against AA, which can restore hematopoietic function by activating mitophagy. The results provide inspiration for the clinical application of traditional Chinese medicine in AA treatment.

Overexpression of REC8 induces aberrant gamete meiotic division and contributes to AML pathogenesis - a multiplexed microarray analysis and mendelian randomization study.

Acute myeloid leukemia (AML) is a notably lethal disease, characterized by malignant clonal proliferation of hematopoietic stem cells in the bone marrow. This study seeks to unveil potential therapeutic targets for AML, using a combined approach of microarray analysis and Mendelian randomization (MR). We collected data samples from the Gene Expression Omnibus (GEO) database and extracted pQTL data from genome-wide association studies (GWAS) to identify overlapping genes between the DEGs and GWAS data. Gene enrichment and pathway annotation analyses were performed on these genes. Furthermore, we validated gene expression levels and assessed their clinical relevance. By taking the intersection of these gene sets, we obtained a list of co-expressed genes, including four upregulated genes (REC8, TPM2, ZMIZ1, CD82) and two downregulated genes (IFNAR1, TMCO3). MR analysis demonstrated that genetically predicted protein levels of CD82, REC8, ZMIZ1, and TPM2 were significantly associated with increased odds of AML, while IFNAR1 and TMCO3 showed a protective effect. Gene ontology and KEGG pathway analyses revealed significant enrichment in functions related to female gamete generation, meiosis, p53 signaling pathway, and cardiac muscle contraction. Differences in immune cell profiles were observed between AML survivors and those with poor prognosis, including lower levels of neutrophils and higher levels of follicular helper T cells in the latter group. This study identifies a causal relationship between gene expression and AML and highlights the potential role of REC8 in leukemogenesis, possibly through its impact on gametocyte meiotic abnormalities. The findings provide new insights into the prevention and treatment of leukemia.

Screening and Activity Evaluation of Novel BCR-ABL/T315I Tyrosine Kinase Inhibitors.

Chronic myeloid leukemia (CML) is a kind of malignant tumor formed by the clonal proliferation of bone marrow hematopoietic stem cells. BCR-ABL fusion protein, found in more than 90% of patients, is a vital target for discovering anti- CML drugs. Up to date, imatinib is the first BCR-ABL tyrosine kinase inhibitor (TKI) approved by the FDA for treating CML. However, the drug resistance problems appeared for many reasons, especially the T135I mutation, a "gatekeeper" of BCR-ABL. Currently, there is no long-term effective and low side effect drug in clinical. This study intends to find novel TKIs targeting BCR-ABL with high inhibitory activity against T315I mutant protein by combining artificial intelligence technology and cell growth curve, cytotoxicity, flow cytometry and Western blot experiments. The obtained compound was found to kill leukemia cells, which had good inhibitory efficacy in BaF3/T315I cells. Compound no 4 could induce cell cycle arrest, cause autophagy and apoptosis, and inhibit the phosphorylation of BCR-ABL tyrosine kinase, STAT5 and Crkl proteins. The results indicated that the screened compound could be used as a lead compound for further research to discover ideal chronic myeloid leukemia therapeutic drugs.

Phase 3 study of the lysine-specific demethylase 1 (LSD1) inhibitor bomedemstat in patients with essential thrombocythemia (ET).

TPS6596 Background: ET is a myeloproliferative neoplasm (MPN) driven by mutations in JAK2, CALR, and MPL that is characterized by thrombocytosis and megakaryocyte hyperplasia. Currently available treatments can prevent thrombotic complications but do not substantially alter the natural history of ET. LSD1 is an enzyme that regulates hematopoietic stem and progenitor cell proliferation and is overexpressed in MPNs. In a phase 2 study, the LSD1 inhibitor bomedemstat was generally well tolerated and improved symptoms, durably reduced platelet and white blood cell counts, and reduced mutation burden in patients with ET. Here, we describe the methods for a randomized, open-label, phase 3 study (NCT06079879) that has been designed to evaluate bomedemstat versus best available therapy in patients with ET who had an inadequate response to or were intolerant of hydroxyurea. Methods: Key eligibility criteria include age ≥18 years, a diagnosis of ET per World Health Organization 2016 diagnostic criteria, a bone marrow fibrosis score of grade 0 or 1, a platelet count of >450 x 109/L, and an absolute neutrophil count of ≥0.75 x 109/L. All patients must have a history of inadequate response to or intolerance of hydroxyurea per modified European LeukemiaNet (ELN) criteria. Patients will be randomly assigned 1:1 to bomedemstat 50 mg/day by mouth (starting dose) or investigator’s choice of best available therapy (anagrelide, busulfan, interferon alfa/pegylated interferon alpha, or ruxolitinib). Bomedemstat dose will be titrated to a target platelet count of ≥150 to ≤350 x 109/L. After 52 weeks, patients receiving best available therapy can cross over to bomedemstat at the investigator’s discretion and patients in the bomedemstat arm can continue on treatment (maximum of 156 weeks on study). Randomization will be stratified by hydroxyurea history (inadequate response vs intolerance) and MFSAF v4.0 baseline score (≥4 vs <4). Clinic visits will occur every 2 weeks until week 12 and monthly thereafter. Adverse events will be graded per NCI CTCAE v5.0 criteria and monitored for up to 30 days after last dose of study drug. The primary end point is durable clinicohematologic response rate per modified ELN criteria. Secondary end points are duration of clinicohematologic response, duration of hematologic remission, change from baseline in total symptom and fatigue score per MFSAF v4.0 criteria, change from baseline in total fatigue score per the PROMIS Fatigue SF-7a scale, incidence of thrombotic or major hemorrhagic events, transformation to post-ET myelofibrosis or myelodysplastic syndrome/acute myeloid leukemia, event-free survival, and safety. Exploratory end points include pharmacokinetics, the proportion of patients reporting stability or improvement versus decline on the MSAF v4.0 and PROMIS Fatigue SF-7a domains, and molecular biomarkers. Approximately 300 patients will be enrolled. Clinical trial information: NCT06079879 .

Increased CXCL10 (IP-10) is associated with advanced myeloproliferative neoplasms and its loss dampens erythrocytosis in mouse models

Key studies in pre-leukemic disorders have linked increases in pro-inflammatory cytokines with accelerated phases of the disease, but the precise role of the cellular microenvironment in disease initiation and evolution remains poorly understood. In myeloproliferative neoplasms (MPNs), higher levels of specific cytokines have been previously correlated with increased disease severity (tumor necrosis factor-alpha [TNF-α], interferon gamma-induced protein-10 [IP-10 or CXCL10]) and decreased survival (interleukin 8 [IL-8]). Whereas TNF-α and IL-8 have been studied by numerous groups, there is a relative paucity of studies on IP-10 (CXCL10). Here we explore the relationship of IP-10 levels with detailed genomic and clinical data and undertake a complementary cytokine screen alongside functional assays in a wide range of MPN mouse models. Similar to patients, levels of IP-10 were increased in mice with more severe disease phenotypes (e.g., JAK2V617F/V617F TET2-/- double-mutant mice) compared with those with less severe phenotypes (e.g., CALRdel52 or JAK2+/V617F mice) and wild-type (WT) littermate controls. Although exposure to IP-10 did not directly alter proliferation or survival in single hematopoietic stem cells (HSCs) in vitro, IP-10-/- mice transplanted with disease-initiating HSCs developed an MPN phenotype more slowly, suggesting that the effect of IP-10 loss was noncell-autonomous. To explore the broader effects of IP-10 loss, we crossed IP-10-/- mice into a series of MPN mouse models and showed that its loss reduces the erythrocytosis observed in mice with the most severe phenotype. Together, these data point to a potential role for blocking IP-10 activity in the management of MPNs.

Not just for lymphoid cells: the role of the noncanonical NF-κB signaling pathway in early and late myelopoiesis with a focus on hypereosinophilic disorders.

The noncanonical NF-κB pathway is involved in lymphoid organ development, B-cell maturation, and cytokine production. However, new research has demonstrated that this pathway is also key for the orderly and sequential maturation of myeloid cells, including neutrophils and eosinophils. When this pathway is disrupted or constitutively activated, aberrations in hematopoietic stem and progenitor cell survival and proliferation, as well as subsequent granulopoiesis and eosinophilopoiesis, are affected. Disturbance of such a coordinated and delicate process can manifest in devastating clinical disease, including acute and chronic myeloid leukemias, preleukemic processes such as myelodysplastic syndrome, or hyperinflammatory conditions like hypereosinophilic syndrome. In this review, we discuss the molecular machinery within the noncanonical NF-κB pathway, crosstalk with the canonical NF-κB pathway, murine models of noncanonical signaling, and how aberrations in this pathway manifest in leukemic or hyperinflammatory disease with a focus on hypereosinophilic syndrome. Potential and promising drug therapies will also be discussed, emphasizing the noncanonical NF-κB pathway as a potential target for improved treatment for patients with leukemia or idiopathic hypereosinophilic syndrome. The hope is that review of such mechanisms and treatments may eventually result in findings that aid physicians in rapidly diagnosing and more accurately classifying patients with such complex and overlapping hematopoietic diseases.

Advances in Molecular Understanding of Polycythemia Vera, Essential Thrombocythemia, and Primary Myelofibrosis: Towards Precision Medicine.

Myeloproliferative neoplasms (MPNs), including Polycythemia Vera (PV), Essential Thrombocythemia (ET), and Primary Myelofibrosis (PMF), are characterized by the clonal proliferation of hematopoietic stem cells leading to an overproduction of hematopoietic cells. The last two decades have seen significant advances in our understanding of the molecular pathogenesis of these diseases, with the discovery of key mutations in the JAK2, CALR, and MPL genes being pivotal. This review provides a comprehensive update on the molecular landscape of PV, ET, and PMF, highlighting the diagnostic, prognostic, and therapeutic implications of these genetic findings. We delve into the challenges of diagnosing and treating patients with prognostic mutations, clonal evolution, and the impact of emerging technologies like next-generation sequencing and single-cell genomics on the field. The future of MPN management lies in leveraging these molecular insights to develop personalized treatment strategies, aiming for precision medicine that optimizes outcomes for patients. This article synthesizes current knowledge on molecular diagnostics in MPNs, underscoring the critical role of genetic profiling in enhancing patient care and pointing towards future research directions that promise to further refine our approach to these complex disorders.

Cytogenetic and epidemiological profile of chronic myeloid leukemia in Morocco.

Chronic myeloid leukemia (CML) is a neoplastic disease of genetic origin resulting from clonal proliferation of hematopoietic stem cells (HSCs). The reciprocal translocation t(9;22)(q34;q11) is the main chromosomal abnormality involved in this pathology, usually detected by conventional cytogenetics. This article aims to investigate the epidemiological, cytogenetic, therapeutic, and clinical characteristics of Moroccan patients with CML. This research represents the first large-scale study of CML patients in Morocco and was carried out at Institut Pasteur of Morocco. Bone marrow samples were processed for cytogenetic analysis, and karyotypes were described according to an international system of human cytogenetic nomenclature (ISCN 2016). Patients were studied according to their epidemiological characteristics, clinical information and cytogenetic results. For statistical calculations, R version 4.3.1 was used to analyze the data and calculate the statistical parameters. RStudio and Power BI were used for data visualization. The National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) method of incidence estimation was used to calculate our incidence. We received 826 patients (from 1992 to 2023) who were referred for suspected CML or who were undergoing treatment. Only 650 patients with confirmed CML were included in the study, all of whom underwent their first cytogenetic test. The median age of our patients was 45 years and the sex ratio was 1.03. At the time of diagnosis, 147 (30%) of the patients had clinical manifestations. Most patients were diagnosed in the chronic phase (94.5%). Nineteen complex variant translocations of the Philadelphia (Ph) chromosome were detected. At the time of diagnosis, 55 (11.5%) patients had ACAs, of which 30 (54.5%) were high-risk ACAs. Based on data from 174 patients treated with imatinib, the median time to complete cytogenetic response (CCyR) was 11 months, and at the last cytogenetic follow-up, 81 patients (46.6%) achieved CCyR, while 64 patients (36.8%) showed no response to treatment. Regarding adherence to European LeukemiaNet (ELN) guidelines, 58 patients (33%) were followed according to these guidelines, with optimal treatment in 8.6%, suboptimal treatment in 7% and treatment failure in 18%. The estimated incidence of chronic myeloid leukemia calculated is 0.6 cases per 100,000 in the Casablanca region. This study provides a detailed overview of CML in Morocco, highlighting important clinical, cytogenetic and therapeutic aspects despite some limitations. It also highlights the need to deepen our understanding of this complex disease for disease management in our specific context.

EGFR-dependent endocytosis of Wnt9a and Fzd9b promotes β-catenin signaling during hematopoietic stem cell development in zebrafish.

Cell-to-cell communication through secreted Wnt ligands that bind to members of the Frizzled (Fzd) family of transmembrane receptors is critical for development and homeostasis. Wnt9a signals through Fzd9b, the co-receptor LRP5 or LRP6 (LRP5/6), and the epidermal growth factor receptor (EGFR) to promote early proliferation of zebrafish and human hematopoietic stem cells during development. Here, we developed fluorescently labeled, biologically active Wnt9a and Fzd9b fusion proteins to demonstrate that EGFR-dependent endocytosis of the ligand-receptor complex was required for signaling. In human cells, the Wnt9a-Fzd9b complex was rapidly endocytosed and trafficked through early and late endosomes, lysosomes, and the endoplasmic reticulum. Using small-molecule inhibitors and genetic and knockdown approaches, we found that Wnt9a-Fzd9b endocytosis required EGFR-mediated phosphorylation of the Fzd9b tail, caveolin, and the scaffolding protein EGFR protein substrate 15 (EPS15). LRP5/6 and the downstream signaling component AXIN were required for Wnt9a-Fzd9b signaling but not for endocytosis. Knockdown or loss of EPS15 impaired hematopoietic stem cell development in zebrafish. Other Wnt ligands do not require endocytosis for signaling activity, implying that specific modes of endocytosis and trafficking may represent a method by which Wnt-Fzd specificity is established.

Study of Patterns of Leukaemia in a Tertiary Care Hospital

Introduction: Leukaemia arises from abnormal proliferation of hematopoietic or lymphoid cells, categorized as acute or chronic and originating from lymphoid, myeloid, or mixed lineages. Clinical manifestations result from leukemic cell proliferation and tissue infiltration. Objectives: This study aimed to determine the frequency and clinicopathological profile of leukaemia cases. Material and Methods: A three-year cross-sectional observational study was carried out in the Department of Pathology, Indira Gandhi Medical College, Shimla. Diagnosis of Leukaemia was based on complete blood count, peripheral smear examination, bone marrow analysis and cytochemistry wherever required. Data comprising of patient details, clinical examination and haematological parameters were analysed. Results: A total of 163 leukaemia cases were identified, including 102 (63%) acute and 61(37%) cases of chronic leukaemia. Acute leukaemia consisted of 58 cases of Acute Myeloid Leukaemia (AML), 25 Acute Lymphoblastic Leukaemia (ALL), and 19 undifferentiated leukaemia (UL), while chronic cases comprised 47 Chronic Myeloid Leukaemia (CML) and 14 Chronic Lymphocytic Leukaemia (CLL). Most patients were in the age group of 31-60 years, with a male predominance (M:F 1.7:1). Conclusions: Early diagnosis and typing are vital for prompt leukaemia treatment. Despite advanced technologies, cytomorphological examination with cytochemistry remains crucial, especially in resource-limited settings like India. Keywords: Leukaemia, acute, chronic, cytomorphology, observational study

Identification of hub genes and potential molecular mechanisms related to drug sensitivity in acute myeloid leukemia based on machine learning.

Background: Acute myeloid leukemia (AML) is the most common form of leukemia among adults and is characterized by uncontrolled proliferation and clonal expansion of hematopoietic cells. There has been a significant improvement in the treatment of younger patients, however, prognosis in the elderly AML patients remains poor. Methods: We used computational methods and machine learning (ML) techniques to identify and explore the differential high-risk genes (DHRGs) in AML. The DHRGs were explored through multiple in silico approaches including genomic and functional analysis, survival analysis, immune infiltration, miRNA co-expression and stemness features analyses to reveal their prognostic importance in AML. Furthermore, using different ML algorithms, prognostic models were constructed and validated using the DHRGs. At the end molecular docking studies were performed to identify potential drug candidates targeting the selected DHRGs. Results: We identified a total of 80 DHRGs by comparing the differentially expressed genes derived between AML patients and normal controls and high-risk AML genes identified by Cox regression. Genetic and epigenetic alteration analyses of the DHRGs revealed a significant association of their copy number variations and methylation status with overall survival (OS) of AML patients. Out of the 137 models constructed using different ML algorithms, the combination of Ridge and plsRcox maintained the highest mean C-index and was used to build the final model. When AML patients were classified into low- and high-risk groups based on DHRGs, the low-risk group had significantly longer OS in the AML training and validation cohorts. Furthermore, immune infiltration, miRNA coexpression, stemness feature and hallmark pathway analyses revealed significant differences in the prognosis of the low- and high-risk AML groups. Drug sensitivity and molecular docking studies revealed top 5 drugs, including carboplatin and austocystin-D that may significantly affect the DHRGs in AML. Conclusion: The findings from the current study identified a set of high-risk genes that may be used as prognostic and therapeutic markers for AML patients. In addition, significant use of the ML algorithms in constructing and validating the prognostic models in AML was demonstrated. Although our study used extensive bioinformatics and machine learning methods to identify the hub genes in AML, their experimental validations using knock-out/-in methods would strengthen our findings.

HES6 knockdown in human hematopoietic precursor cells reduces their in vivo engraftment potential and their capacity to differentiate into erythroid cells, B cells, T cells and plasmacytoid dendritic cells.

Hematopoiesis is driven by molecular mechanisms that induce differentiation and proliferation of hematopoietic stem cells and their progeny. This involves the activity of various transcription factors, such as members of the Hairy/Enhancer of Split (HES) family, and important roles for both HES1 and HES4 have been shown in normal and malignant hematopoiesis. Here, we investigated the role of HES6 in human hematopoiesis using in vitro and in vivo models. Using bulk and scRNA-seq data, we show that HES6 is expressed during erythroid/megakaryocyte and pDC development, as well as in multipotent precursors and at specific stages of T- and B-cell development following preBCR and preTCR signalling, respectively. Consistently, knockdown of HES6 in cord blood-derived hematopoietic precursors in well-defined in vitro differentiation assays resulted in reduced differentiation of human hematopoietic precursors towards megakaryocytes, erythrocytes, pDCs, Band T-cells. In addition, HES6 knockdown HSPCs displayed reduced colony forming unit capacity in vitro and impaired potential to reconstitute hematopoiesis in vivo in a competitive transplantation assay. We demonstrate that loss of HES6 expression impacts cell cycle progression during erythroid differentiation and provide evidence for potential downstream target genes that impact these perturbations. Thus, our study uncovers new insights for a role of HES6 in human hematopoiesis.

Gum hypertrophy in acute myeloid leukemia: an important clinical finding not to be missed

Acute myeloid leukaemia (AML) is characterized by disordered differentiation and proliferation of abnormal hematopoietic stem cells. AML usually presents with symptoms of anemia like pallor and fatigue, recurrent infections, petechiae, and mucosal bleeds. Extramedullary infiltration of leukemic cells is a common finding like proptosis or myeloid sarcoma. The occurrence of gingival hypertrophy in the pediatric age group is uncommon and usually due to inflammation followed by prolonged use of certain drugs like cyclosporin or phenytoin. Gingival infiltration in AML is rare in children, usually associated with subtypes M4/M5 (FAB classification). This case report highlights the importance of considering AML as an important differential diagnosis in cases of gum hypertrophy, as being a less common cause, it is often overlooked. Timely diagnosis and prompt treatment can be lifesaving. Here, we report two cases who presented with gum hypertrophy.

Abstract 4664: Therapeutic targeting of TP53-mutated acute myeloid leukemia by inhibiting cell cycle checkpoint

Abstract Acute myeloid leukemia (AML) is a hematological malignancy characterized by various somatic mutations leading to abnormal proliferation and differentiation of hematopoietic cells. Mutations on the TP53 gene occur in 5% to 10% of patients with de novo AML, with higher frequency in patients with relapsed and refractory (R/R) AML. Patients with TP53-mutated AML typically exhibit a poor response to conventional induction therapy and have a short overall survival (OS) rate, with a median duration of 5-9 months. Although various target agents have been developed for the treatment of AML, treatment options for TP53-mutated AML remain limited. Here, we have discovered a novel drug combination that can enhance the efficacy of the conventional therapeutic regimen for TP53-mutated AML patients. For in vitro analysis, we used the human AML cell line Kasumi-1(AML-M2), which harbors a homozygous TP53 R248Q mutation. We treated kasumi-1 cells with a combination of cytarabine and Idarubicin to produce drug tolerant persisters (DTPs) which is a minor population that survived the drug treatment. The Kasumi-1 DTPs displayed temporal G2/M phase cell cycle arrest and significant resistance to further repeated drug treatment. To discover drug candidates targeting TP53-mutated DTPs, we first examined the differentially expressed genes (DEGs) of TP53-mutated AML patients using patients’ RNA expression data deposited in the cancer genome atlas (TCGA) database. Using selected DEGs, drug candidates potentially affecting TP53-mutated AML cells were extracted from the connectivity map (CMap build 02) database. In addition, through a literature search, drugs with the ability to reactivate mutant p53, drugs that directly target mutant p53, synthetic lethal partners with mutant p53, and drugs that target leukemia stem cells were selected as candidate groups. As a result, we selected 46 drug candidates that would be effective for TP53-mutated AML through in silico analysis and therapy strategies targeting p53. Using in vitro cytotoxicity assay, we screened 46 candidate compounds at multiple doses and confirmed several drugs that effectively eliminate DTPs. The drug screening showed that cell cycle checkpoint inhibitors not only resulted in a significant reduction of G2/M phase arrested cells but also induction of apoptotic cells at the subG1 phase. Furthermore, the zero interaction potency (ZIP) model of SynergyFinder (https://synergyfinder.fimm.fi) analysis showed that cell cycle checkpoint inhibitors synergistically enhanced the cytotoxic effect of cytarabine on Kasumi-1 DTPs. Collectively, this study suggests that novel combination treatment of cell cycle checkpoint inhibitors with conventional drugs selectively inhibits TP53-mutated AML DTPs. Citation Format: Daehyeon Gwak, Dongchan Kim, Heejun Jang, Jun Liu, Suji Min, Ja Min Byun, Youngil Koh, Junshik Hong, Sung-soo Yoon, Dong-Yeop Shin, Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea, Republic of. Therapeutic targeting of TP53-mutated acute myeloid leukemia by inhibiting cell cycle checkpoint [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4664.

Abstract 4595: HSK41959-2: An oral MTA-cooperative PRMT5 inhibitor for MTAP deleted cancer

Abstract Methylthioadenosine phosphorylase (MTAP) homozygous deletion occurs in 10-15% of all human cancers. Loss of MTAP result in methylthioadenosine (MTA) accumulation. PRMT5, which is a type II arginine methyltransferase that regulates multiple essential cellular functions via symmetric dimethylation of arginine (SDMA) in target proteins, was identified as a synthetic lethal target for MTAP del cancers. MTA-cooperative PRMT5 inhibitors may exhibit better safety profiling compared to first generation PRMT5i (which observe limiting heme-related toxicities in clinical), which preferentially inhibiting PRMT5 in MTAP del cancer cells to normal cells. HSK41959-2 is a MTA-cooperative PRMT5 inhibitor, which could selectively inhibits PRMT5 in the present of MTA with IC50 was 0.80 nM. In HCT116 MTAP Deleted cell line, HSK41959-2 significantly inhibits the cell proliferation with GI50 of 19.89 nM, which was around 45-fold selectivity in HCT116 cell line. In SDMA assay, HSK41959-2 also showed high potency in HCT116 MTAP-del cell line with IC50 was 3.39 nM, and much weaker in HCT116 MTAP-WT cell line with IC50 was 499 nM, around 147-fold selectivity. In vitro CD34+ Hematopoietic stem cell cell proliferation assay was used for evaluate the heme-related toxicities. HSK41959-2 weakly inhibited the cell proliferation with IC50 of 544 nM while the first generation PRMT5i with IC50 was 35.39 nM. This results indicated HSK41959-2 may has lower heme-related toxicities compared with the first generation PRMT5i. In the HCT116 MTAP-del xenograft model, daily orally administrated with 25 mpk and 100 mpk HSK41959-2 showed significant tumor growth inhibition, with TGI were 62% and 88%, and PRMT5-dependent SDMA protein inhibition were 89% and 95%, respectively. Meanwhile in the HCT116 MTAP-WT xenograft model, HSK41959-2 did not show tumor growth inhibition at 100 mpk. In conclusion, HSK41959-2 is a promising oral MTA-cooperative PRMT5 inhibitor, it was nominated as a development candidate. Citation Format: Pangke Yan, Ju Wang, Meilin Qian, Xiaojuan Yu, Yao Li, Haoliang Zhang, Lihua Tao, Rui Kou, Teng Hu, Pingming Tang, Hongjiao Dong, Aipin Wu, Maotao He. HSK41959-2: An oral MTA-cooperative PRMT5 inhibitor for MTAP deleted cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4595.

Interleukin 3 Inhibits Glutamate-Cytotoxicity in Neuroblastoma Cell Line.

Interleukin 3 (IL-3) is a well-known pleiotropic cytokine that regulates the proliferation and differentiation of hematopoietic progenitor cells, triggering classical signaling pathways such as JAK/STAT, Ras/MAPK, and PI3K/Akt to carry out its functions. Interestingly, the IL-3 receptor is also expressed in non-hematopoietic cells, playing a crucial role in cell survival. Our previous research demonstrated the expression of the IL-3 receptor in neuron cells and its protective role in neurodegeneration. Glutamate, a principal neurotransmitter in the central nervous system, can induce cellular stress and lead to neurotoxicity when its extracellular concentrations surpass normal levels. This excessive glutamate presence is frequently observed in various neurological diseases. In this study, we uncover the protective role of IL-3 as an inhibitor of glutamate-induced cell death, analyzing the cytokine's signaling pathways during its protective effect. Specifically, we examined the relevance of JAK/STAT, Ras/MAPK, and PI3 K signaling pathways in the molecular mechanism triggered by IL-3. Our results show that the inhibition of JAK, ERK, and PI3 K signaling pathways, using pharmacological inhibitors, effectively blocked IL-3's protective role against glutamate-induced cell death. Additionally, our findings suggest that Bcl-2 and Bax proteins may be involved in the molecular mechanism triggered by IL-3. Our investigation into IL-3's ability to protect neuronal cells from glutamate-induced damage offers a promising therapeutic avenue with potential clinical implications for several neurological diseases characterized by glutamate neurotoxicity.

Landscape of FLT3 Variations Associated with Structural and Functional Impact on Acute Myeloid Leukemia: A Computational Study.

Acute myeloid leukemia (AML) is hallmarked by the clonal proliferation of myeloid blasts. Mutations that result in the constitutive activation of the fms-like tyrosine kinase 3 (FLT3) gene, coding for a class III receptor tyrosine kinase, are significantly associated with this heterogeneous hematologic malignancy. The fms-related tyrosine kinase 3 ligand binds to the extracellular domain of the FLT3 receptor, inducing homodimer formation in the plasma membrane, leading to autophosphorylation and activation of apoptosis, proliferation, and differentiation of hematopoietic cells in bone marrow. In the present study, we evaluated the association of FLT3 as a significant biomarker for AML and tried to comprehend the effects of specific variations on the FLT3 protein's structure and function. We also examined the effects of I836 variants on binding affinity to sorafenib using molecular docking. We integrated multiple bioinformatics tools, databases, and resources such as OncoDB, UniProt, COSMIC, UALCAN, PyMOL, ProSA, Missense3D, InterProScan, SIFT, PolyPhen, and PredictSNP to annotate the structural, functional, and phenotypic impact of the known variations associated with FLT3. Twenty-nine FLT3 variants were analyzed using in silico approaches such as DynaMut, CUPSAT, AutoDock, and Discovery Studio for their impact on protein stability, flexibility, function, and binding affinity. The OncoDB and UALCAN portals confirmed the association of FLT3 gene expression and its mutational status with AML. A computational structural analysis of the deleterious variants of FLT3 revealed I863F mutants as destabilizers of the protein structure, possibly leading to functional changes. Many single-nucleotide variations in FLT3 have an impact on its structure and function. Thus, the annotation of FLT3 SNVs and the prediction of their deleterious pathogenic impact will facilitate an insight into the tumorigenesis process and guide experimental studies and clinical implications.