-
Nature Communications Jul 2024Despite the development of novel therapies for acute myeloid leukemia, outcomes remain poor for most patients, and therapeutic improvements are an urgent unmet need....
Despite the development of novel therapies for acute myeloid leukemia, outcomes remain poor for most patients, and therapeutic improvements are an urgent unmet need. Although treatment regimens promoting differentiation have succeeded in the treatment of acute promyelocytic leukemia, their role in other acute myeloid leukemia subtypes needs to be explored. Here we identify and characterize two lysine deacetylase inhibitors, CM-444 and CM-1758, exhibiting the capacity to promote myeloid differentiation in all acute myeloid leukemia subtypes at low non-cytotoxic doses, unlike other commercial histone deacetylase inhibitors. Analyzing the acetylome after CM-444 and CM-1758 treatment reveals modulation of non-histone proteins involved in the enhancer-promoter chromatin regulatory complex, including bromodomain proteins. This acetylation is essential for enhancing the expression of key transcription factors directly involved in the differentiation therapy induced by CM-444/CM-1758 in acute myeloid leukemia. In summary, these compounds may represent effective differentiation-based therapeutic agents across acute myeloid leukemia subtypes with a potential mechanism for the treatment of acute myeloid leukemia.
Topics: Humans; Cell Differentiation; Leukemia, Myeloid, Acute; Epigenesis, Genetic; Histone Deacetylase Inhibitors; Cell Line, Tumor; Acetylation; Transcription Factors; Gene Expression Regulation, Leukemic; Animals
PubMed: 38956053
DOI: 10.1038/s41467-024-49784-y -
Biomedicine & Pharmacotherapy =... Jul 2024T-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematological disorder characterized by an increased proliferation of immature T lymphocytes precursors. T-ALL...
T-cell acute lymphoblastic leukemia (T-ALL) is a malignant hematological disorder characterized by an increased proliferation of immature T lymphocytes precursors. T-ALL treatment includes chemotherapy with strong side effects, and patients that undergo relapse display poor prognosis. Although cell-intrinsic oncogenic pathways are well-studied, the tumor microenvironment, like inflammatory cellular and molecular components is less explored in T-ALL. We sought to determine the composition of the inflammatory microenvironment induced by T-ALL, and its role in T-ALL progression. We show in two mouse T-ALL cell models that T-ALLs enhance blood neutrophils and resident monocytes, accompanied with a plasmatic acute secretion of inflammatory molecules. Depleting neutrophils using anti-Ly6G treatment or resident monocytes by clodronate liposomes treatment does not modulate plasmatic inflammatory molecule secretion and mice survival. However, inhibiting the secretion of inflammatory molecules by microenvironment with NECA, an agonist of adenosine receptors, diminishes T-ALL progression enhancing mouse survival. We uncovered Hepatocyte Growth Factor (HGF), T-ALL-driven and the most decreased molecule with NECA, as a potential therapeutic target in T-ALL. Altogether, we identified a signature of inflammatory molecules that can potentially be involved in T-ALL evolution and uncovered HGF/cMET pathway as important to target for limiting T-ALL progression.
PubMed: 38955085
DOI: 10.1016/j.biopha.2024.117039 -
Scientific Reports Jul 2024Morgana is a ubiquitous HSP90 co-chaperone protein coded by the CHORDC1 gene. Morgana heterozygous mice develop with age a myeloid malignancy resembling human atypical...
Morgana is a ubiquitous HSP90 co-chaperone protein coded by the CHORDC1 gene. Morgana heterozygous mice develop with age a myeloid malignancy resembling human atypical myeloid leukemia (aCML), now renamed MDS/MPN with neutrophilia. Patients affected by this pathology exhibit low Morgana levels in the bone marrow (BM), suggesting that Morgana downregulation plays a causative role in the human malignancy. A decrease in Morgana expression levels is also evident in the BM of a subgroup of Philadelphia-positive (Ph+) chronic myeloid leukemia (CML) patients showing resistance or an incomplete response to imatinib. Despite the relevance of these data, the mechanism through which Morgana expression is downregulated in patients' bone marrow remains unclear. In this study, we investigated the possibility that Morgana expression is regulated by miRNAs and we demonstrated that Morgana is under the control of four miRNAs (miR-15a/b and miR-26a/b) and that miR-15a may account for Morgana downregulation in CML patients.
Topics: MicroRNAs; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Humans; HSP90 Heat-Shock Proteins; Animals; Mice; Gene Expression Regulation, Leukemic; Down-Regulation; Bone Marrow; Molecular Chaperones
PubMed: 38956394
DOI: 10.1038/s41598-024-65404-7 -
Journal of Cancer Education : the... Jul 2024Patient education in acute myeloid leukemia (AML) has become increasingly complex with the introduction of new treatments and chemotherapy regimens. Video education...
Patient education in acute myeloid leukemia (AML) has become increasingly complex with the introduction of new treatments and chemotherapy regimens. Video education presents an opportunity to supplement traditional patient education and address some of the gaps associated with standard methods. This single-center study sought to assess the potential impact of supplemental video education on patients receiving induction chemotherapy for AML. Participants were consented to be randomized to receive their education with or without a supplemental video designed for their treatment regimen. We then provided a survey to each participant to assess knowledge retention, anxiety, and overall satisfaction with their care. Patients that received video education were found to have significantly improved knowledge retention compared to those that did not. There were no differences detected in anxiety or patient satisfaction. Video education appears to be an effective supplemental method for patient education in AML. Limitations include the single-center nature of the study at an urban academic medical center with a relatively well-educated, primarily Caucasian, younger population. Future research is warranted to assess the video in a diverse set of languages and to explore its broader benefits.
PubMed: 38955941
DOI: 10.1007/s13187-024-02473-2 -
Blood Advances Jul 2024The leukemic stem cell (LSC) score LSC-17 based on a stemness-related gene expression signature is an indicator of poor disease outcome in acute myeloid leukemia (AML)....
The leukemic stem cell (LSC) score LSC-17 based on a stemness-related gene expression signature is an indicator of poor disease outcome in acute myeloid leukemia (AML). However, our understanding of the relationships between LSC and pre-leukemic cells is still incomplete. In particular, it is not known whether "niche-anchoring" of pre-leukemic cell affects disease evolution. To address this issue, we conditionally inactivated the adhesion molecule JAM-C expressed by haematopoietic stem cells (HSC) and LSC in an inducible iMLL-AF9-driven AML mouse model. Deletion of Jam3 (encoding JAM-C) before induction of the leukemia-initiating iMLL-AF9 fusion resulted in a shift from long term to short term-HSC expansion, without affecting disease initiation and progression. In vitro experiments showed that JAM-C controlled leukemic cell nesting irrespective of the bone marrow stromal cells used. RNA sequencing performed on leukemic HSC isolated from diseased mice revealed that genes upregulated in Jam3-deficient animals belonged to Activation Protein-1 (AP-1) and TNF-/NFB pathways. Human orthologs of dysregulated genes allowed to identify a score based on AP-1/TNF-a gene expression that was distinct and complementary from LSC-17 score. Sub-stratification of AML patients with LSC-17 and AP-1/TNF-genes signature defined four groups with median survival ranging from below one year to a median not reached after 8 years. Finally, coculture experiments showed that AP-1 activation in leukemic cells was dependent on the nature of stromal cells. Altogether, our results identify the AP-1/TNF- gene signature as a proxy of LSC anchoring in specific bone marrow niches which improves the prognosis value of the LSC-17 score. NCT02320656.
PubMed: 38954834
DOI: 10.1182/bloodadvances.2023011747 -
In Silico Drug Repurposing Against PSMB8 as a Potential Target for Acute Myeloid Leukemia Treatment.Molecular Biotechnology Jul 2024PSMB8 emerges as a prominent gene associated with cancer survival, yet its potential therapeutic role in acute myeloid leukemia (AML) remains unexplored within the...
PSMB8 emerges as a prominent gene associated with cancer survival, yet its potential therapeutic role in acute myeloid leukemia (AML) remains unexplored within the existing literature. The principal aim of this study is to systematically screen an expansive library of molecular entities, curated from various databases to identify the prospective inhibitory agents with an affinity for PSMB8. A comprehensive assortment of molecular compounds obtained from the ZINC15 database was subjected to molecular docking simulations with PSMB8 by using the AutoDock tool in PyRx (version 0.9.9) to elucidate binding affinities. Following the docking simulations, a select subset of molecules underwent further investigation through comprehensive ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis employing AdmetSar and SwissADME tools. Finally, RMSD, RMSF, Rg, and H bond analyses were conducted via GROMACS to determine the best conformationally dynamic molecule that represents the candidate agent for the study. Following rigorous evaluation, Adozelesin, Fiduxosin, and Rimegepant have been singled out based on considerations encompassing bioavailability scores, compliance with filter criteria, and acute oral toxicity levels. Additionally, ligand interaction analysis indicates that Adozelesin and Fiduxosin exhibit an augmented propensity for hydrogen bond formation, a factor recognized for its facilitative role in protein-ligand interactions. After final analyses, we report that Fiduxosin may offer a treatment possibility by reversing the low survival rates caused by PSMB8 high activation in AML. This study represents a strategic attempt to repurpose readily available pharmaceutical agents, potentially obviating the need for de novo drug development, and thereby offering promising avenues for therapeutic intervention in specific diseases.
PubMed: 38954355
DOI: 10.1007/s12033-024-01224-4 -
Oncotarget Jul 2024
Topics: Humans; DEAD-box RNA Helicases; Animals; Leukemia, Myeloid; Mice
PubMed: 38953908
DOI: 10.18632/oncotarget.28603 -
Pediatric Blood & Cancer Jul 2024The molecular pathogenesis of acute myeloid leukemia (AML) was dramatically clarified over the latest two decades. Several important molecular markers were discovered in...
High DOCK1 expression identifies a distinct prognostic subgroup of pediatric acute myeloid leukemia: Results of the Japanese Pediatric Leukemia/Lymphoma Study Group AML-05 trial.
BACKGROUND
The molecular pathogenesis of acute myeloid leukemia (AML) was dramatically clarified over the latest two decades. Several important molecular markers were discovered in patients with AML that have helped to improve the risk stratification. However, developing new treatment strategies for relapsed/refractory acute myeloid leukemia (AML) is crucial due to its poor prognosis.
PROCEDURE
To overcome this difficulty, we performed an assay for transposase-accessible chromatin with sequencing (ATAC-seq) in 10 AML patients with various gene alterations. ATAC-seq is based on direct in vitro sequencing adaptor transposition into native chromatin, and is a rapid and sensitive method for integrative epigenomic analysis. ATAC-seq analysis revealed increased accessibility of the DOCK1 gene in patients with AML harboring poor prognostic factors. Following the ATAC-seq results, quantitative reverse transcription polymerase chain reaction was used to measure DOCK1 gene expression levels in 369 pediatric patients with de novo AML.
RESULTS
High DOCK1 expression was detected in 132 (37%) patients. The overall survival (OS) and event-free survival (EFS) among patients with high DOCK1 expression were significantly worse than those patients with low DOCK1 expression (3-year EFS: 34% vs. 60%, p < .001 and 3-year OS: 60% vs. 80%, p < .001). To investigate the significance of high DOCK1 gene expression, we transduced DOCK1 into MOLM14 cells, and revealed that cytarabine in combination with DOCK1 inhibitor reduced the viability of these leukemic cells.
CONCLUSIONS
Our results indicate that a DOCK1 inhibitor might reinforce the effects of cytarabine and other anti-cancer agents in patients with AML with high DOCK1 expression.
PubMed: 38953149
DOI: 10.1002/pbc.31151 -
Leukemia Research Reports 2024Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy associated with various combinations of gene mutations, epigenetic abnormalities, and chromosome...
Acute myeloid leukemia (AML) is a heterogeneous hematological malignancy associated with various combinations of gene mutations, epigenetic abnormalities, and chromosome rearrangement-related gene fusions. Despite the significant degree of heterogeneity in its pathogenesis, many gene fusions and point mutations are recurrent in AML and have been employed in risk stratification over the last several decades. Gene fusions have long been recognized for understanding tumorigenesis and their proven roles in clinical diagnosis and targeted therapies. Advances in DNA sequencing technologies and computational biology have contributed significantly to the detection of known fusion genes as well as for the discovery of novel ones. Several recurring gene fusions in AML have been linked to prognosis, treatment response, and disease progression. In this report, we present a case with a long history of essential thrombocythemia and hallmark mutation transforming to AML characterized by a previously unreported fusion gene. We propose mechanisms by which this fusion may contribute to the pathogenesis of AML and its potential as a molecular target for tyrosine kinase inhibitors.
PubMed: 38952949
DOI: 10.1016/j.lrr.2024.100465 -
Pakistan Journal of Medical Sciences Jul 2024Mixed-phenotype acute leukemia (MPAL) is rare in the clinic, accounting for approximately 2%-5% of acute leukemia cases. (Review)
Review
OBJECTIVES
Mixed-phenotype acute leukemia (MPAL) is rare in the clinic, accounting for approximately 2%-5% of acute leukemia cases.
METHODS
In this study the cohort included 126 patients, of which 125 cases were from re-examined published data and current patients from Shenzhen Longhua District Central Hospital, carrying an ETV6-ABL1 rearrangement from April 15, 2020 to December 19, 2020. The ETS variant transcription factor 6-Abelson proto-oncogene 1 (ETV6-ABL1) fusion gene is mainly seen in malignant hematological diseases such as acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), myeloproliferative neoplasms (MPNs). Positivity of both MPAL and ETV6-ABL1 suggest a poor prognosis. This is the first report of B lymphocytic/myeloid mixed-phenotype acute leukemia with ETV6-ABL1 fusion gene positivity. Complete remission was achieved with chemotherapy for lymphoid and myeloid leukemia and targeted therapy with tyrosine kinase inhibitors (TKIs).
RESULTS
The level of ETV6-ABL1/ABL decreased from 23.056% to 11.165%. After consolidation chemotherapy, the patient underwent allogeneic hematopoietic stem cell transplantation but died due to intestinal rejection. There are 126 cases of ETV6-ABL1 fusion gene transcript expression in numerous hematologic malignancies reported to date, including 48 cases of ALL, 12 of AML, and 65 of MPN. Eosinophilia is a common characteristic, especially in MPN patients.
CONCLUSION
Survival analysis suggests that the survival time of ALL and MPN patients receiving TKI treatment is better than that of patients not receiving this treatment. Dasatinib or nilotinib, especially the former, is more effective than imatinib for MPN.
PubMed: 38952502
DOI: 10.12669/pjms.40.6.8497