AML
Ontology highlight
ABSTRACT:
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| ERR322000.fastq.gz | Fastqsanger.gz | |||
| ERR322000_1.fastq.gz | Fastqsanger.gz | |||
| ERR322000_2.fastq.gz | Fastqsanger.gz | |||
| ERR322001.fastq.gz | Fastqsanger.gz | |||
| ERR322002.fastq.gz | Fastqsanger.gz |
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Project description:The heterogeneity of acute myeloid leukaemia (AML) and myelodysplastic syndromes (MDS) has led to a multiplicity of treatments, from cytotoxic agents to signal transduction modulators, cell-cycle inhibitors and epigenetic therapies. While some have shown promising initial results, the outlook for AML patients, particularly older and relapsed patients, as well as patients whose cells exhibit certain adverse chromosomal abnormalities or mutant oncoproteins, continues to be grim. Combination chemotherapy using new agents that act at a number of different levels may provide the greatest potential for successful future therapies. A select number of new agents, approaches and combinations are reviewed here.
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Project description:The use of low dose hypomethylating agents for patients with myelodysplastic syndrome (MDS) and secondary acute myeloid leukemia (AML) has had made a significant impact. In the past, therapies for these diseases were limited and patients who elected to receive treatment were subject to highly toxic, inpatient chemotherapeutics, which were often ineffective. In the era of hypomethylating agents (azacitidine and decitabine), a patient with high grade MDS or AML with multilineage dysplasia can be offered the alternative of outpatient, relatively low-toxicity therapy. Despite the fact that CR (CR) rates to such agents remain relatively low at 15-20%, a much larger percentage of patients will have clinically significant improvements in hemoglobin, platelet, and neutrophil counts while maintaining good outpatient quality of life. As our clinical experience with azanucleotides expands, questions regarding patient selection, optimal dosing strategy, latency to best response and optimal duration of therapy following disease progression remain, but there is no question that for some patients these agents offer, for a time, an almost miraculous clinical benefit. Ongoing clinical trials in combination and in sequence with conventional therapeutics, with other epigenetically active agents, or in conjunction with bone marrow transplantation continue to provide promise for optimization of these agents for patients with myeloid disease. Although the mechanism(s) responsible for the proven efficacy of these agents remain a matter of some controversy, activity is thought to stem from induction of DNA hypomethylation, direct DNA damage, or possibly even immune modulation; there is no question that they have become a permanent part of the armamentarium against myeloid neoplasms.
| S-EPMC4086806 | biostudies-other
Project description:The nonobese diabetic/severe combined immunodeficient (NOD/SCID) assay is the current model for assessment of human normal and leukemic stem cells. We explored why 51% of 59 acute myeloid leukemia (AML) patients were unable to initiate leukemia in NOD/SCID mice. Increasing the cell dose, using more permissive recipients, and alternative tissue sources did not cause AML engraftment in most previously nonengrafting AML samples. Homing of AML cells to the marrow was the same between engrafters and nonengrafters. FLT3 internal tandem duplication (ITD) and nucleophosmin mutations occurred at a similar frequency in engrafters and nonengrafters. The only variable that was related to engraftment ability was the karyotypically defined risk stratification of individual AML cases. Of interest, follow-up of younger patients with intermediate-risk AML revealed a significant difference in overall survival between NOD/SCID engrafting and nonengrafting AMLs. Hence, the ability of AML to engraft in the NOD/SCID assay seems to be an inherent property of AML cells, independent of homing, conditioning, or cell frequency/source, which is directly related to prognosis. Our results suggest an important difference between leukemic initiating cells between engrafting and nonengrafting AML cases that correlates with treatment response.
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Project description:AML patients under the age of 60 whose blasts harbor a FLT3 internal tandem duplication (ITD) mutation have a higher relapse rate and inferior survival compared to those without this mutation. To determine if FLT3ITD also carries a negative prognostic impact in older adults receiving therapies commonly used in this age group, we retrospectively analyzed outcomes of patients ?60 years with CN-AML according to FLT3 mutation status. We identified 91 newly diagnosed CN-AML patients, 55 with wild-type FLT3 and 36 with FLT3ITD. Of the 91 patients, 36 received supportive care and/or experimental therapies while the remaining 55 received induction chemotherapy, followed by allogeneic SCT in 17 of these patients. Based on univariate analysis, advanced age at diagnosis was significantly associated with shorter overall survival (OS) (p<.0001) while intensive therapies were associated with improved OS (p<.0001). In a multivariate analysis that accounted for type of treatment, patient age, gender, and WBC count, FLT3ITD was significantly associated with shorter OS compared to wtFLT3 [p=.001; hazard ratio (HR)=2.23; 95% CI: 1.35-3.70]. Our data support the negative prognostic impact of FLT3ITD in older adults with CN-AML.
| S-EPMC3498766 | biostudies-literature
Project description:The basic leucine zipper transcription factor CCAAT/enhancer binding protein alpha (CEBPA) codes for a critical regulator during neutrophil differentiation. Aberrant expression or function of this protein contributes to the development of acute myeloid leukemia (AML). In this study, we identified two novel unrelated CEBPA target genes, the glycolytic enzyme hexokinase 3 (HK3) and the krüppel-like factor 5 (KLF5) transcription factor, by comparing gene profiles in two cohorts of CEBPA wild-type and mutant AML patients. In addition, we found CEBPA-dependent activation of HK3 and KLF5 transcription during all-trans retinoic acid (ATRA) mediated neutrophil differentiation of acute promyelocytic leukemia (APL) cells. Moreover, we observed direct regulation of HK3 by CEBPA, whereas our data suggest an indirect regulation of KLF5 by this transcription factor. Altogether, our data provide an explanation for low HK3 and KLF5 expression in particular AML subtype and establish these genes as novel CEBPA targets during neutrophil differentiation.
| S-EPMC3939455 | biostudies-literature
Project description:The crosstalk between cancer and stromal cells plays a critical role in tumor progression. Syntenin is a small scaffold protein involved in the regulation of intercellular communication that is emerging as a target for cancer therapy. Here, we show that certain aggressive forms of acute myeloid leukemia (AML) reduce the expression of syntenin in bone marrow stromal cells (BMSC). Stromal syntenin deficiency, in turn, generates a pro-tumoral microenvironment. From serial transplantations in mice and co-culture experiments, we conclude that syntenin-deficient BMSC stimulate AML aggressiveness by promoting AML cell survival and protein synthesis. This pro-tumoral activity is supported by increased expression of endoglin, a classical marker of BMSC, which in trans stimulates AML translational activity. In short, our study reveals a vicious signaling loop potentially at the heart of AML-stroma crosstalk and unsuspected tumor-suppressive effects of syntenin that need to be considered during systemic targeting of syntenin in cancer therapy.
| S-SCDT-10_15252-EMMM_202317570 | biostudies-other
Project description:Severe congenital neutropenia (SCN) is an inborn disorder of granulopoiesis. Like most other bone marrow failure syndromes, it is associated with a marked propensity to transform into a myelodysplastic syndrome (MDS) or acute leukemia, with a cumulative rate of transformation to MDS/leukemia that exceeds 20%. The genetic (and/or epigenetic) changes that contribute to malignant transformation in SCN are largely unknown. In this study, we performed mutational profiling of 14 genes previously implicated in leukemogenesis using 14 MDS/leukemia samples from patients with SCN. We used high-throughput exon-based resequencing of whole-genome-amplified genomic DNA with a semiautomated method to detect mutations. The sensitivity and specificity of the sequencing pipeline was validated by determining the frequency of mutations in these 14 genes using 188 de novo AML samples. As expected, mutations of tyrosine kinase genes (FLT3, KIT, and JAK2) were common in de novo AML, with a cumulative frequency of 30%. In contrast, no mutations in these genes were detected in the SCN samples; instead, mutations of CSF3R, encoding the G-CSF receptor, were common. These data support the hypothesis that mutations of CSF3R may provide the "activated tyrosine kinase signal" that is thought to be important for leukemogenesis.
| S-EPMC1975847 | biostudies-other
Project description:The interaction between the bone marrow microenvironment and malignant hematopoietic cells can result in the protection of leukemia cells from chemotherapy in both myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). We, herein, characterized the changes in cytokine expression and the function of mesenchymal stromal cells (MSC) in patients with MDS, AML with myelodysplasia-related changes (MRC), a well-recognized clinical subtype of secondary AML, and de novo AML. We observed a significant inhibitory effect of MDS-MSC on T lymphocyte proliferation and no significant differences in any of the cytokines tested. AML-MSC inhibited T-cell proliferation only at a very low MSC/T cell ratio. When compared to the control, AML-MRCderived MSC presented a significant increase in IL6 expression, whereas de novo AML MSC presented a significant increase in the expression levels of VEGFA, CXCL12, RPGE2, IDO, IL1β, IL6 and IL32, followed by a decrease in IL10 expression. Furthermore, data indicate that IL-32 regulates stromal cell proliferation, has a chemotactic potential and participates in stromal cell crosstalk with leukemia cells, which could result in chemoresistance. Our results suggest that the differences between AML-MRC and de novo AML also extend into the leukemic stem cell niche and that IL-32 can participate in the regulation of the bone marrow cytokine milieu.
| S-EPMC5234038 | biostudies-literature
Project description:PurposeInfections due to severe neutropenia are the most common therapy-associated causes of mortality in patients with acute myeloid leukemia (AML). New strategies to lessen the severity and duration of neutropenia are needed.MethodsCytarabine is commonly used for AML consolidation therapy; we compared high- and intermediate-dose cytarabine administration on days 1, 2, and 3 (AC-123) versus days 1, 3, and 5 (AC-135) in consolidation therapy of AML. Recently, clinical trials demonstrated that high-dose AC-123 resulted in a shortened white blood cell (WBC) recovery time compared with high-dose AC-135. Our main hypothesis is that this is also the case for different cytarabine dosage, granulocyte colony-stimulating factor (G-CSF) administration, and cycle lengths. We analyzed 334 treatment schedules on virtual cohorts of digital twins.ResultsComparison of 32,565 simulated consolidation cycles resulted in a reduction in the WBC recovery time for AC-123 in 99.6% of the considered cycles (median reduction 3.5 days) without an increase in the number of leukemic blasts (lower value in 94.2% of all cycles), compared to AC-135.ConclusionOur numerical study supports the use of AC-123 plus G-CSF as standard conventional AML consolidation therapy to reduce the risk for life-threatening infectious complications.
| S-EPMC10590325 | biostudies-literature
Project description:Multiple new drugs are being developed to treat acute myeloid leukemia (AML), including novel formulations of traditional chemotherapy-antibody drug conjugates and agents that target specific mutant enzymes. Next-generation sequencing has allowed us to discover the genetic mutations that lead to the development and clinical progression of AML. Studies of clonal hierarchy suggest which mutations occur early and dominate. This has led to targeted therapy against mutant driver proteins as well as the development of drugs such as CPX-351 and SGN-CD33A whose mechanisms of action and efficacy may not be dependent on mutational complexity. In this brief review, we discuss drugs that may emerge as important for the treatment of AML in the next 10 years.
| S-EPMC4915807 | biostudies-literature