scholarly journals Role and Importance of Inflammasomes and Immune Pathways in Myeloid Malignancies, Particularly Myelodysplastic Syndromes (MDS)/Acute Myeloid Leukemia (AML) to Better Understand the Disease Pathophysiology and Decipher the Scope of Therapeutic Interventions

2021 ◽  
pp. 825-867
Author(s):  
Ricardo Gobato ◽  
Abhijit Mitra
Keyword(s):  
Cancer Research ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Therapeutic Interventions ◽  
Tumor Spread ◽  
Cancer Research Institute ◽  
Keywords Cancer ◽  
Immune Pathways ◽  
Acute Myeloid ◽  
Research Institute

Thanks to work by researchers at the California South University (CSU) Cancer Research Institute (CRI), they may soon have new tools to treat melanoma and other cancers. In an article published last month, members of the Cancer Research Institute (CRI) introduced an intracellular complex. Involved in melanoma-mediated inflammation and leads to tumor growth and progression. The researchers found that by inhibiting NLRP3, they could reduce inflammation and tumor spread. Keywords: Cancer; Cells; Tissues; Tumors; Prevention; Prognosis; Diagnosis; Imaging; Screening, Treatment; Management

scholarly journals Therapeutic Potential of Pharmacological Targeting NLRP3 Inflammasome Complex in Cancer Using Inhibition of NLRP3 Inflammasome in Tumor Microenvironment Leads to Suppression of Metastatic Potential of Cancer Cells

2021 ◽  
pp. 833-873
Author(s):  
Elena Locci ◽  
Silvia Raymond
Keyword(s):  
Cancer Research ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Nlrp3 Inflammasome ◽  
Therapeutic Potential ◽  
Metastatic Potential ◽  
Tumor Spread ◽  
Cancer Research Institute ◽  
Keywords Cancer ◽  
Research Institute

Thanks to work by researchers at the California South University (CSU) Cancer Research Institute (CRI), they may soon have new tools to treat melanoma and other cancers. In an article published last month, members of the Cancer Research Institute (CRI) introduced an intracellular complex. Involved in melanoma-mediated inflammation and leads to tumor growth and progression. The researchers found that by inhibiting NLRP3, they could reduce inflammation and tumor spread. Keywords: Cancer; Cells; Tissues, Tumors; Prevention, Prognosis; Diagnosis; Imaging; Screening; Treatment; Management

scholarly journals Combined inhibition of JAK/STAT pathway and lysine-specific demethylase 1 as a therapeutic strategy in CSF3R/CEBPA mutant acute myeloid leukemia

2020 ◽  
Vol 117 (24) ◽  
pp. 13670-13679 ◽  
Author(s):  
Theodore P. Braun ◽  
Cody Coblentz ◽  
Brittany M. Smith ◽  
Daniel J. Coleman ◽  
Zachary Schonrock ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Therapeutic Strategy ◽  
Hematologic Malignancy ◽  
Therapeutic Interventions ◽  
Leukemia Cells ◽  
Lysine Specific Demethylase ◽  
Increased Risk ◽  
Stat Signaling ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a deadly hematologic malignancy with poor prognosis, particularly in the elderly. Even among individuals with favorable-risk disease, approximately half will relapse with conventional therapy. In this clinical circumstance, the determinants of relapse are unclear, and there are no therapeutic interventions that can prevent recurrent disease. Mutations in the transcription factor CEBPA are associated with favorable risk in AML. However, mutations in the growth factor receptor CSF3R are commonly co-occurrent in CEBPA mutant AML and are associated with an increased risk of relapse. To develop therapeutic strategies for this disease subset, we performed medium-throughput drug screening on CEBPA/CSF3R mutant leukemia cells and identified sensitivity to inhibitors of lysine-specific demethylase 1 (LSD1). Treatment of CSF3R/CEBPA mutant leukemia cells with LSD1 inhibitors reactivates differentiation-associated enhancers driving immunophenotypic and morphologic differentiation. LSD1 inhibition is ineffective as monotherapy but demonstrates synergy with inhibitors of JAK/STAT signaling, doubling median survival in vivo. These results demonstrate that combined inhibition of JAK/STAT signaling and LSD1 is a promising therapeutic strategy for CEBPA/CSF3R mutant AML.

scholarly journals Extramedullary Disease in Adult Acute Myeloid Leukemia Is Common but Lacks Independent Significance: Analysis of Patients in ECOG-ACRIN Cancer Research Group Trials, 1980-2008

2016 ◽  
Vol 34 (29) ◽  
pp. 3544-3553 ◽  
Author(s):  
Chezi Ganzel ◽  
Judith Manola ◽  
Dan Douer ◽  
Jacob M. Rowe ◽  
Hugo F. Fernandez ◽  
...  
Keyword(s):  
Cancer Research ◽  
Overall Survival ◽  
Clinical Trials ◽  
Acute Myeloid Leukemia ◽  
Prognostic Factors ◽  
Research Group ◽  
Large Study ◽  
Myeloid Leukemia ◽  
Extramedullary Disease ◽  
Acute Myeloid

Purpose Extramedullary disease (EMD) at diagnosis in patients with acute myeloid leukemia (AML) has been recognized for decades. Reported herein are results from a large study of patients with AML who were treated in consecutive ECOG-ACRIN Cancer Research Group frontline clinical trials in an attempt to define the incidence and clinical implications of EMD. Methods Patients with newly diagnosed AML, age 15 years and older, who were treated in 11 clinical trials, were studied to identify EMD, as defined by physical examination, laboratory findings, and imaging results. Results Of the 3,522 patients enrolled, 282 were excluded, including patients with acute promyelocytic leukemia, incorrect diagnosis, or no adequate assessment of EMD at baseline. The overall incidence of EMD was 23.7%. The sites involved were: lymph nodes (11.5%), spleen (7.3%), liver (5.3%), skin (4.5%), gingiva (4.4%), and CNS (1.1%). Most patients (65.3%) had only one site of EMD, 20.9% had two sites, 9.5% had three sites, and 3.4% had four sites. The median overall survival was 1.035 years. In univariable analysis, the presence of any EMD ( P = .005), skin involvement ( P = .002), spleen ( P < .001), and liver ( P < .001), but not CNS ( P = .34), nodal involvement ( P = .94), and gingival hypertrophy ( P = .24), was associated with a shorter overall survival. In contrast, in multivariable analysis, adjusted for known prognostic factors such as cytogenetic risk and WBC count, neither the presence of EMD nor the number of specific sites of EMD were independently prognostic. Conclusion This large study demonstrates that EMD at any site is common but is not an independent prognostic factor. Treatment decisions for patients with EMD should be made on the basis of recognized AML prognostic factors, irrespective of the presence of EMD.

scholarly journals Targeted Therapies and Druggable Genetic Anomalies in Acute Myeloid Leukemia: From Diagnostic Tools to Therapeutic Interventions

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4698
Author(s):  
Francesco Lanza ◽  
Ali Bazarbachi
Keyword(s):  
Acute Myeloid Leukemia ◽  
Progenitor Cells ◽  
Targeted Therapies ◽  
Myeloid Leukemia ◽  
Somatic Mutations ◽  
Therapeutic Interventions ◽  
Hematopoietic Progenitor Cells ◽  
Diagnostic Tools ◽  
Hematopoietic Progenitor ◽  
Acute Myeloid

Acute myeloid leukemia (AML) is a clonal disorder resulting from acquired somatic mutations in hematopoietic progenitor cells that lead to the dysregulation of differentiation and the proliferation of hematopoietic cells [...]

scholarly journals Lysosomes in acute myeloid leukemia: potential therapeutic targets?

Leukemia ◽  
2021 ◽  
Author(s):  
Sreoshee Rafiq ◽  
Sharon L. McKenna ◽  
Sylviane Muller ◽  
Mario P. Tschan ◽  
Magali Humbert
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Unmet Need ◽  
Therapeutic Interventions ◽  
Cellular Functions ◽  
Genomic Landscape ◽  
Nutrient Signaling ◽  
Clinical Interest ◽  
Acute Myeloid

AbstractLysosomes, since their discovery, have been primarily known for degrading cellular macromolecules. However, in recent studies, they have begun to emerge as crucial regulators of cell homeostasis. They are at the crossroads of catabolic and anabolic pathways and are intricately involved in cellular trafficking, nutrient signaling, energy metabolism, and immune regulation. Their involvement in such essential cellular functions has renewed clinical interest in targeting the lysosome as a novel way to treat disease, particularly cancer. Acute myeloid leukemia (AML) is an aggressive blood cancer with a low survival probability, particularly in older patients. The genomic landscape of AML has been extensively characterized but few targeted therapies (with the exception of differentiation therapy) can achieve a long-term cure. Therefore, there is an unmet need for less intensive and more tolerable therapeutic interventions. In this review, we will give an overview on the myriad of functions performed by lysosomes and their importance in malignant disease. Furthermore, we will discuss their relevance in hematopoietic cells and different ways to potentially target them in AML.

Epitranscriptomic modifications in acute myeloid leukemia: m6A and 2′-O-methylation as targets for novel therapeutic strategies

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Cornelius Pauli ◽  
Michael Kienhöfer ◽  
Stefanie Göllner ◽  
Carsten Müller-Tidow
Keyword(s):  
Acute Myeloid Leukemia ◽  
Ribosomal Rna ◽  
Myeloid Leukemia ◽  
Current Knowledge ◽  
Therapeutic Strategies ◽  
Therapeutic Interventions ◽  
Rna Modifications ◽  
Novel Therapeutic Strategies ◽  
Acute Myeloid

Abstract Modifications of RNA commonly occur in all species. Multiple enzymes are involved as writers, erasers and readers of these modifications. Many RNA modifications or the respective enzymes are associated with human disease and especially cancer. Currently, the mechanisms how RNA modifications impact on a large number of intracellular processes are emerging and knowledge about the pathogenetic role of RNA modifications increases. In Acute Myeloid Leukemia (AML), the N 6-methyladenosine (m6A) modification has emerged as an important modulator of leukemogenesis. The writer proteins METTL3 and METTL14 are both involved in AML pathogenesis and might be suitable therapeutic targets. Recently, close links between 2′-O-methylation (2′-O-me) of ribosomal RNA and leukemogenesis were discovered. The AML1-ETO oncofusion protein which specifically occurs in a subset of AML was found to depend on induction of snoRNAs and 2′-O-me for leukemogenesis. Also, NPM1, an important tumor suppressor in AML, was associated with altered snoRNAs and 2′-O-me. These findings point toward novel pathogenetic mechanisms and potential therapeutic interventions. The current knowledge and the implications are the topic of this review.

Identification of the Novel Chromosomal Translocation t(17;19)(q23;q13) in a Pediatric Patient with Acute Myeloid Leukemia.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4344-4344
Author(s):  
Deborah L. Shardy ◽  
Mohammed F. Azim ◽  
Rizwan C. Naeem ◽  
Sharon E. Plon
Keyword(s):  
Acute Myeloid Leukemia ◽  
Reciprocal Translocation ◽  
Myeloid Leukemia ◽  
Bone Marrow Cells ◽  
Residual Disease ◽  
Chromosomal Translocation ◽  
Therapeutic Interventions ◽  
High Dose ◽  
Artificial Chromosomes ◽  
Acute Myeloid

Abstract Chromosomal rearrangements have been associated with many hematologic malignancies. Identification of the genes involved in several of these rearrangements has provided information about the development of malignancy and has led to therapeutic interventions. Historically, a considerable number of pediatric acute myeloid leukemia (AML) cases have been reported as cytogenetically normal. However, with improved cytogenetic techniques and the use of fluorescent in situ hybridization (FISH), new translocations are now being identified. We present the case of a 10-year-old male with AML (FAB subtype M1) and a subtle chromosomal translocation. G-band karyotype analysis revealed a balanced, reciprocal translocation between chromosomes 17 and 19 involving bands 17q23 and 19q13. This translocation was present in 20 out of 20 bone marrow cells examined. Peripheral blood chromosome analysis ruled out a constitutional chromosomal abnormality. Metaphase FISH with telomere-region specific probes for chromosomes 17 and 19 confirmed the reciprocal translocation between 17q and 19q. This patient was treated according to the SJCRH AML 2002 protocol and was randomized to receive high-dose cytarabine. Because he had minimal residual disease following induction therapy, he also received Gemtuzumab Ozogamicin. The patient was in cytogenetic remission for one year after completion of therapy, and then he relapsed with the original leukemic clone and additional cytogenetic abnormalities. The t(17;19)(q23;q13) has not been reported previously in malignancies or other disorders, and therefore identification of the genes at the chromosomal breakpoints may provide new insights into the pathogenesis of AML. As an initial step to map the breakpoint regions, we performed FISH with a commercially available probe encompassing the CRX, GLTSCR2, and GLTSCR1 loci on 19q13 (Vysis, Downers Grove, IL). This revealed that the 19q breakpoint is centromeric to these loci. We are further mapping the translocation breakpoint region on chromosome 19q using FISH-mapped bacterial artificial chromosomes (BACs).

scholarly journals Prognostic Significance of NPM1 Mutations in the Absence of FLT3–Internal Tandem Duplication in Older Patients With Acute Myeloid Leukemia: A SWOG and UK National Cancer Research Institute/Medical Research Council Report

2015 ◽  
Vol 33 (10) ◽  
pp. 1157-1164 ◽  
Author(s):  
Fabiana Ostronoff ◽  
Megan Othus ◽  
Michelle Lazenby ◽  
Elihu Estey ◽  
Frederick R. Appelbaum ◽  
...  
Keyword(s):  
Cancer Research ◽  
Older Patients ◽  
Myeloid Leukemia ◽  
Research Council ◽  
Medical Research Council ◽  
Prognostic Significance ◽  
Cancer Research Institute ◽  
National Cancer Research Institute ◽  
The Impact ◽  
Acute Myeloid

Purpose Younger patients with acute myeloid leukemia (AML) harboring NPM1 mutations without FLT3–internal tandem duplications (ITDs; NPM1-positive/FLT3-ITD–negative genotype) are classified as better risk; however, it remains uncertain whether this favorable classification can be applied to older patients with AML with this genotype. Therefore, we examined the impact of age on the prognostic significance of NPM1-positive/FLT3-ITD–negative status in older patients with AML. Patients and Methods Patients with AML age ≥ 55 years treated with intensive chemotherapy as part of Southwest Oncology Gorup (SWOG) and UK National Cancer Research Institute/Medical Research Council (NCRI/MRC) trials were evaluated. A comprehensive analysis first examined 156 patients treated in SWOG trials. Validation analyses then examined 1,258 patients treated in MRC/NCRI trials. Univariable and multivariable analyses were used to determine the impact of age on the prognostic significance of NPM1 mutations, FLT3-ITDs, and the NPM1-positive/FLT3-ITD–negative genotype. Results Patients with AML age 55 to 65 years with NPM1-positive/FLT3-ITD–negative genotype treated in SWOG trials had a significantly improved 2-year overall survival (OS) as compared with those without this genotype (70% v 32%; P < .001). Moreover, patients age 55 to 65 years with NPM1-positive/FLT3-ITD–negative genotype had a significantly improved 2-year OS as compared with those age > 65 years with this genotype (70% v 27%; P < .001); any potential survival benefit of this genotype in patients age > 65 years was marginal (27% v 16%; P = .33). In multivariable analysis, NPM1-positive/FLT3-ITD–negative genotype remained independently associated with an improved OS in patients age 55 to 65 years (P = .002) but not in those age > 65 years (P = .82). These results were confirmed in validation analyses examining the NCRI/MRC patients. Conclusion NPM1-positive/FLT3-ITD–negative genotype remains a relatively favorable prognostic factor for patients with AML age 55 to 65 years but not in those age > 65 years.

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