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Biomedicine & Pharmacotherapy =... Jun 2024Over the last decade, discovery of novel therapeutic method has been attention by the researchers and has changed the therapeutic perspective of hematological... (Review)
Review
Over the last decade, discovery of novel therapeutic method has been attention by the researchers and has changed the therapeutic perspective of hematological malignancies. Although NK cell play a pivotal role in the elimination of abnormal and cancerous cells, there are evidence that NK cell are disarm in hematological malignancy. Chimeric antigen receptor NK (CAR-NK) cell therapy, which includes the engineering of NK cells to detect tumor-specific antigens and, as a result, clear of cancerous cells, has created various clinical advantage for several human malignancies treatment. In the current review, we summarized NK cell dysfunction and CAR-NK cell based immunotherapy to treat AML patient.
PubMed: 38941897
DOI: 10.1016/j.biopha.2024.117024 -
Leukemia Jun 2024RNA constitutes a large fraction of chromatin. Spatial distribution and functional relevance of most of RNA-chromatin interactions remain unknown. We established a...
RNA constitutes a large fraction of chromatin. Spatial distribution and functional relevance of most of RNA-chromatin interactions remain unknown. We established a landscape analysis of RNA-chromatin interactions in human acute myeloid leukemia (AML). In total more than 50 million interactions were captured in an AML cell line. Protein-coding mRNAs and long non-coding RNAs exhibited a substantial number of interactions with chromatin in cis suggesting transcriptional activity. In contrast, small nucleolar RNAs (snoRNAs) and small nuclear RNAs (snRNAs) associated with chromatin predominantly in trans suggesting chromatin specific functions. Of note, snoRNA-chromatin interaction was associated with chromatin modifications and occurred independently of the classical snoRNA-RNP complex. Two C/D box snoRNAs, namely SNORD118 and SNORD3A, displayed high frequency of trans-association with chromatin. The transcription of SNORD118 and SNORD3A was increased upon leukemia transformation and enriched in leukemia stem cells, but decreased during myeloid differentiation. Suppression of SNORD118 and SNORD3A impaired leukemia cell proliferation and colony forming capacity in AML cell lines and primary patient samples. Notably, this effect was leukemia specific with less impact on healthy CD34+ hematopoietic stem and progenitor cells. These findings highlight the functional importance of chromatin-associated RNAs overall and in particular of SNORD118 and SNORD3A in maintaining leukemia propagation.
PubMed: 38942785
DOI: 10.1038/s41375-024-02322-7 -
IL-9 Secreted by Leukemia Stem Cells Induces Th1-Skewed CD4+ T-Cells, which Promote Their Expansion.Blood Jun 2024In acute myeloid leukemia (AML), leukemia stem and progenitor cells (LSCs and LPCs) interact with various cell types in the bone marrow (BM) microenvironment, regulating...
In acute myeloid leukemia (AML), leukemia stem and progenitor cells (LSCs and LPCs) interact with various cell types in the bone marrow (BM) microenvironment, regulating their expansion and differentiation. To study the interaction of CD4+ and CD8+ T-cells in the BM with LSCs and LPCs, we analyzed their transcriptome and predicted cell-cell interactions by unbiased high-throughput correlation network analysis. We found that CD4+ T-cells in the BM of AML patients were activated and skewed towards Th1-polarization whereas IL-9 producing (Th9) CD4+ T-cells were absent. In contrast to normal hematopoietic stem cells (HSCs), LSCs produced IL-9 and the correlation modelling predicted IL9 in LSCs as a main hub-gene that activates CD4+ T-cells in AML. Functional validation revealed that IL-9R signaling in CD4+ T-cells leads to activation of the JAK-STAT pathway that induces the upregulation of KMT2A, KMT2C genes resulting in methylation on histone H3 at lysine 4 (H3K4) to promote genome accessibility and transcriptional activation. This induced Th1-skewing, proliferation and effector cytokine secretion, including interferon (IFN)-ɣ and tumor necrosis factor (TNF)-α. IFN-ɣ and to a lesser extend TNF-α produced by activated CD4+ T-cells, induced the expansion of LSCs. In accordance with our findings, high IL9 expression in LSCs and high IL9R, TNF and IFNG expression in BM-infiltrating CD4+ T-cells correlated with worse overall survival in AML. Thus, IL-9 secreted by AML LSCs shapes a Th1-skewed immune environment that promotes their expansion by secreting IFN-ɣ and TNF-α.
PubMed: 38941612
DOI: 10.1182/blood.2024024000 -
Blood Advances Jun 2024While intensive induction chemotherapy (IC) remains the standard of care for younger patients with acute myeloid leukemia (AML), data from older patients shows that...
While intensive induction chemotherapy (IC) remains the standard of care for younger patients with acute myeloid leukemia (AML), data from older patients shows that hypomethylating agents + venetoclax (HMA/VEN) can lead to durable remissions among patients with NPM1 mutations. Whether IC or HMA/VEN is superior in patients ≥60 years-old with NPM1-mutant AML is unknown. To compare IC and HMA/VEN, we performed an international, multicenter retrospective cohort study of patients with newly diagnosed, NPM1-mutant AML.We included 221 patients (147 IC, 74 HMA/VEN) with previously untreated NPM1-mutant AML. Composite complete remission (cCR; defined as CR + CR with incomplete count recovery [CRi]) rate was similar for IC and HMA/VEN (cCR: 85% vs. 74%; p=0.067). While OS was favorable with IC in unselected patients compared to HMA/VEN (24-month OS 59% [95% CI: 52-69%] vs. 38% [95% CI 27-55%]; p=0.013), it was not statistically different among patients 60-75 years-old (60% [95% CI 52-70%] vs. 44% [95% CI 29-66%]; p=0.069) and patients who received an allogeneic stem cell transplant (70% [95% CI: 58-85%] vs. 66% [95% CI: 44-100%]; p=0.56). Subgroup analyses suggested that patients with normal cytogenetics (24-month OS with IC 65% [95% 56-74%] vs. 40% [95% CI: 26-60%] with HMA/VEN; p=0.009) and without FLT3-ITD mutations might benefit from IC compared with HMA/VEN (24-month OS: 68% [95% CI: 59-79%] vs. 43% [95% CI: 29-63%]; p=0.008). In multivariable analysis, OS was not statistically different for patients treated with IC and HMA/VEN (hazard ratio for death HMA/VEN vs. IC: 0.71; 95% CI: 0.40-1.27; p=0.25).
PubMed: 38941537
DOI: 10.1182/bloodadvances.2024012858 -
Journal of Pediatric Hematology/oncology Jun 2024Programmed death-1 (PD1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) have a vital role in immune checkpoint pathways. Single nucleotide polymorphisms (SNPs)...
Relationship Between Cytotoxic T-Lymphocyte-Associated Antigen-4: Programmed Death-1 Genes Polymorphisms and Susceptibility to Pediatric B-Cell Acute Lymphoblastic Leukemia.
Programmed death-1 (PD1) and cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) have a vital role in immune checkpoint pathways. Single nucleotide polymorphisms (SNPs) of PD1 and CTLA4 have been reported to be associated with susceptibility to certain autoimmune diseases and cancers. The potential association between SNPs in these immune checkpoint genes and risk of acute lymphoblastic leukemia (ALL) still unclear. The aim of this study is to clarify the effect of PD1 and CTLA4 SNPs on the risk of developing ALL and the prognosis of the disease. The study was performed on 100 pediatric B-ALL patients and 100 controls. The PD1 and CTLA4 SNPs were examined by RFLP technique. The study revealed that CTLA4 (rs11571316) was associated with high risk of B-ALL developments OR 1.492 (CI: 1157 to 1924) (P=0.002). PD1 (rs36084323) GA genotype was significantly associated with protective effect against nonremission (P=0.007). PD1 (rs36084323) A allele were associated with protective effect against relapse (P=0.008). CTLA4 and PD1 genotypes did not have significant impact on B-ALL patients outcome. The current study displayed for the first time that genetic variations of the CTLA-4, was associated with susceptibility to B-ALL and that PD1 (rs36084323) GA genotype was significantly associated with protective effect against nonremission, while PD1 (rs36084323) A allele was associated with protective effect against relapse.
PubMed: 38940594
DOI: 10.1097/MPH.0000000000002909 -
Frontiers in Bioscience (Scholar... May 2024The ETS transcription factor PU.1 plays an essential role in blood cell development. Its precise expression pattern is governed by cis-regulatory elements (CRE) acting... (Review)
Review
The ETS transcription factor PU.1 plays an essential role in blood cell development. Its precise expression pattern is governed by cis-regulatory elements (CRE) acting at the chromatin level. CREs mediate the fine-tuning of graded levels of , deviations of which can cause acute myeloid leukemia. In this review, we perform an in-depth analysis of the regulation of expression in normal and malignant hematopoiesis. We elaborate on the role of trans-acting factors and the biomolecular interplays in mediating local chromatin dynamics. Moreover, we discuss the current understanding of CRE bifunctionality exhibiting enhancer or silencer activities in different blood cell lineages and future directions toward gene-specific chromatin-targeted therapeutic development.
Topics: Humans; Hematopoiesis; Proto-Oncogene Proteins; Trans-Activators; Cell Lineage; Animals; Transcription, Genetic; Gene Expression Regulation; Leukemia, Myeloid, Acute; Chromatin
PubMed: 38939973
DOI: 10.31083/j.fbs1602010 -
Frontiers in Oncology 2024Infections represent one of the most frequent causes of death of higher-risk MDS patients, as reported previously also by our group. Azacitidine Infection Risk Model...
INTRODUCTION
Infections represent one of the most frequent causes of death of higher-risk MDS patients, as reported previously also by our group. Azacitidine Infection Risk Model (AIR), based on red blood cell (RBC) transfusion dependency, neutropenia <0.8 × 10/L, platelet count <50 × 10/L, albumin <35g/L, and ECOG performance status ≥2 has been proposed based on the retrospective data to estimate the risk of infection in azacitidine treated patients.
METHODS
The prospective non-intervention study aimed to identify factors predisposing to infection, validate the AIR score, and assess the impact of antimicrobial prophylaxis on the outcome of azacitidine-treated MDS/AML and CMML patients.
RESULTS
We collected data on 307 patients, 57.6 % males, treated with azacitidine: AML (37.8%), MDS (55.0%), and CMML (7.1%). The median age at azacitidine treatment commencement was 71 (range, 18-95) years. 200 (65%) patients were assigned to higher risk AIR group. Antibacterial, antifungal, and antiviral prophylaxis was used in 66.0%, 29.3%, and 25.7% of patients, respectively. In total, 169 infectious episodes (IE) were recorded in 118 (38.4%) patients within the first three azacitidine cycles. In a multivariate analysis ECOG status, RBC transfusion dependency, IPSS-R score, and CRP concentration were statistically significant for infection development ( < 0.05). The occurrence of infection within the first three azacitidine cycles was significantly higher in the higher risk AIR group - 47.0% than in lower risk 22.4% (odds ratio (OR) 3.06; 95% CI 1.82-5.30, < 0.05). Administration of antimicrobial prophylaxis did not have a significant impact on all-infection occurrence in multivariate analysis: antibacterial prophylaxis (OR 0.93; 0.41-2.05, = 0.87), antifungal OR 1.24 (0.54-2.85) ( = 0.59), antiviral OR 1.24 (0.53-2.82) ( = 0.60).
DISCUSSION
The AIR Model effectively discriminates infection-risk patients during azacitidine treatment. Antimicrobial prophylaxis does not decrease the infection rate.
PubMed: 38939343
DOI: 10.3389/fonc.2024.1404322 -
Frontiers in Oncology 2024This study aims to elucidate the clinical features observed in cases of pediatric acute myeloid leukemia (AML) initially presenting with cardiac tamponade and to share...
OBJECTIVE
This study aims to elucidate the clinical features observed in cases of pediatric acute myeloid leukemia (AML) initially presenting with cardiac tamponade and to share treatment experiences.
MATERIALS AND METHODS
Five pediatric patients were initially diagnosed with AML accompanied by cardiac myeloid sarcoma (MS). The diagnosis was established by examining our hospital records and reviewing pertinent literature from 1990 to July 2023, accessible through MEDLINE/PubMed. We comprehensively assessed the clinical characteristics and treatment modalities employed for these patients.
RESULT
Five pediatric patients presented with acute symptoms, including shortness of breath, malaise, cough, and fever, leading to their hospitalization. Physical examination revealed irritability, hypoxia, tachypnea, tachycardia, and hypotension. Initial detection utilized chest X-ray or echocardiogram, leading to subsequent diagnoses based on pericardial effusion and/or bone marrow examination. Two patients received chemotherapy at the time of initial diagnosis, one with cytarabine and etoposide, and the other with cytarabine and cladribine. Post-treatment, their bone marrow achieved remission, and over a 2.5-year follow-up, their cardiac function remained favorable. Unfortunately, the remaining three patients succumbed within two weeks after diagnosis, either due to receiving alternative drugs or without undergoing chemotherapy.
CONCLUSION
This is the first and largest case series of pediatric AML patients with cardiac MS, manifesting initially with cardiac tamponade. It highlights the rarity and high mortality associated with this condition. The critical factors for reducing mortality include identifying clinical manifestations, conducting thorough physical examinations, performing echocardiography promptly, initiating early and timely pericardial drainage, and avoiding cardiotoxic chemotherapy medications.
PubMed: 38939339
DOI: 10.3389/fonc.2024.1391768 -
Frontiers in Oncology 2024Acute myeloid leukemia (AML) with hyperleukocytosis (HL) is a severe medical emergency associated with high mortality rates and poor prognosis. Prompt and urgent...
BACKGROUND
Acute myeloid leukemia (AML) with hyperleukocytosis (HL) is a severe medical emergency associated with high mortality rates and poor prognosis. Prompt and urgent treatment is crucial to address this medical emergency. This study aims to elucidate appropriate diagnostic thresholds for HL and investigate underlying mechanisms and potential targeted therapies.
METHODS
X-tile software was employed to analyze white blood cell (WBC) count thresholds in AML patients using data from TCGA and TARGET AML databases. METASCAPE and Gene Set Enrichment Analysis (GSEA) were conducted to explore the molecular mechanisms underlying HL in AML. Potential molecular targeted drugs were identified using the CELLMINER platform.
RESULTS
Analysis revealed that a WBC count threshold of 75×10/L, rather than the conventional 100×10/L, is more appropriate for diagnosing HL in adult AML patients. This revised threshold could aid clinicians in identifying a greater number of patients requiring immediate intervention. Significant correlations were observed between HL and specific mutations, including NPM1, FLT3, and DNMT3A. For pediatric AML patients, the HL threshold was determined to be 165×10/L. Achieving complete remission (CR) or deeper levels of remission significantly reduces the risks associated with HL. The reduction in risk can lead to survival outcomes for HL patients that are comparable to those of non-hyperleukocytosis patients. Differential gene expression analysis indicated that downregulation of cell adhesion molecules is implicated in HL pathogenesis. Potential targeted therapies for AML with HL include Bcl2 inhibitors and histone deacetylase inhibitors. Clinical observations demonstrated that the addition of Bcl2 inhibitors, such as Venetoclax, to standard therapy results in a rapid reduction in WBC counts, thereby reducing tumor burden and providing prompt symptom relief. Combining these targeted drugs with conventional therapies appears promising in mitigating risks associated with HL.
CONCLUSIONS
Lower diagnostic thresholds for HL in AML, identifies critical genetic correlations, and highlights effective molecular targeted therapies. Proactive early treatment is crucial for achieving deep remission and reducing HL risk. Future therapeutic strategies should consider integrating molecular targeted drugs with conventional therapies to improve outcomes for patients facing this high-risk hematological emergency.
PubMed: 38939329
DOI: 10.3389/fonc.2024.1412583 -
Cureus May 2024Acute lymphoblastic leukemia (ALL) is the most prevalent pediatric malignancy, accounting for approximately 25% of childhood cancers. Despite significant advancements in...
Acute lymphoblastic leukemia (ALL) is the most prevalent pediatric malignancy, accounting for approximately 25% of childhood cancers. Despite significant advancements in treatment protocols, ALL remains a complex disease, often presenting with various complications, including the rare metabolic disturbance of type B lactic acidosis. This case report details the clinical journey of a 14-year-old female with ALL who developed type B lactic acidosis during treatment. The patient presented with intermittent fever, abdominal pain, jaundice, and hepatosplenomegaly, accompanied by severe anemia and thrombocytopenia. Initial management included supportive care and chemotherapy initiation. Despite aggressive interventions, the patient's condition deteriorated, with escalating lactic acidosis and respiratory distress, leading to a critical need for tailored management strategies. This report underscores the importance of early recognition and comprehensive management of type B lactic acidosis in pediatric ALL, highlighting its multifactorial etiology and potentially life-threatening consequences. Enhanced clinical awareness and a multidisciplinary approach are crucial for improving outcomes in such complex cases.
PubMed: 38939285
DOI: 10.7759/cureus.61201