Targeting RUNX1 in acute myeloid leukemia: preclinical innovations and therapeutic implications

2021 ◽  
pp. 1-11
Author(s):  
Fanny Gonzales ◽  
Adeline Barthélémy ◽  
Pauline Peyrouze ◽  
Laurène Fenwarth ◽  
Claude Preudhomme ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Therapeutic Implications ◽  
Acute Myeloid

scholarly journals Molecular Landscape of Acute Myeloid Leukemia: Prognostic and Therapeutic Implications

2020 ◽  
Vol 22 (6) ◽  
Author(s):  
Ludovica Marando ◽  
Brian J. P. Huntly
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Gene Mutations ◽  
Influence Strategies ◽  
Prognostic Information ◽  
Therapeutic Implications ◽  
Genomic Landscape ◽  
Genetic Landscape ◽  
Molecular Landscape ◽  
Acute Myeloid

Abstract Purpose of Review The field of acute myeloid leukemia (AML) has been revolutionized in recent years by the advent of high-throughput techniques, such as next-generation sequencing. In this review, we will discuss some of the recently identified mutations that have defined a new molecular landscape in this disease, as well as their prognostic, predictive, and therapeutic implications. Recent Findings Recent studies have shown how many cases of AML evolve from a premalignant period of latency characterized by the accumulation of several mutations and the emergence of one or multiple dominant clones. The pattern of co-occurring mutations and cytogenetic abnormalities at diagnosis defines risk and can determine therapeutic approaches to induce remission. Besides the genetic landscape at diagnosis, the continued presence of particular gene mutations during or after treatment carries prognostic information that should further influence strategies to maintain remission in the long term. Summary The recent progress made in AML research is a seminal example of how basic science can translate into improving clinical practice. Our ability to characterize the genomic landscape of individual patients has not only improved our ability to diagnose and prognosticate but is also bringing the promise of precision medicine to fruition in the field.

scholarly journals Acute Myeloid Leukemia with the t(8;21) Translocation: Clinical Consequences and Biological Implications

2011 ◽  
Vol 2011 ◽  
pp. 1-23 ◽  
Author(s):  
Håkon Reikvam ◽  
Kimberley Joanne Hatfield ◽  
Astrid Olsnes Kittang ◽  
Randi Hovland ◽  
Øystein Bruserud
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Fusion Gene ◽  
Good Prognosis ◽  
Leukemic Cells ◽  
Therapeutic Implications ◽  
Clinical Consequences ◽  
Leukemia Relapse ◽  
Acute Myeloid

The t(8;21) abnormality occurs in a minority of acute myeloid leukemia (AML) patients. The translocation results in an in-frame fusion of two genes, resulting in a fusion protein of one N-terminal domain from the AML1 gene and four C-terminal domains from the ETO gene. This protein has multiple effects on the regulation of the proliferation, the differentiation, and the viability of leukemic cells. The translocation can be detected as the only genetic abnormality or as part of more complex abnormalities. If t(8;21) is detected in a patient with bone marrow pathology, the diagnosis AML can be made based on this abnormality alone. t(8;21) is usually associated with a good prognosis. Whether the detection of the fusion gene can be used for evaluation of minimal residual disease and risk of leukemia relapse remains to be clarified. To conclude, detection of t(8;21) is essential for optimal handling of these patients as it has both diagnostic, prognostic, and therapeutic implications.

scholarly journals NPM1 and FLT3-ITD/TKD Gene Mutations in Acute Myeloid Leukemia

2021 ◽  
Author(s):  
Shano Naseem ◽  
Jogeshwar Binota ◽  
Neelam Varma ◽  
Harpreet Virk ◽  
Subhash Varma ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
De Novo ◽  
Gene Mutations ◽  
Total Leucocyte Count ◽  
Molecular Testing ◽  
Therapeutic Implications ◽  
Number Of Patients ◽  
Flt3 Mutations ◽  
Acute Myeloid

Background: A number of mutations have been reported to occur in patients with acute myeloid leukemia (AML), of which NPM1 and FLT3 genes mutations are the commonest and have important diagnostic and therapeutic implications. Material and Methods: Molecular testing for NPM1 and FLT3 genes was performed in 92 de-novo AML patients. The frequency and characteristics of NPM1 and FLT3 mutations were analyzed. Results: Nucleophosmin 1(NPM1) and FMS-like tyrosine kinase 3 (FLT3) mutations were seen in 22.8% and 16.3% of patients, respectively. Amongst FLT3 mutations, FLT3-ITD mutation was seen in 8.7% cases, FLT3- TKD in 5.4%, and FLT3-ITD+TKD in 2.2% cases. Certain associations between the gene mutations and clinical characteristics were found, including in NPM1 mutated group- female preponderance, higher incidence in M4/M5 categories and decreased expression of CD34 and HLA-DR; and in FLT3-ITD mutated group- higher age of presentation, higher total leucocyte count and blast percentage. Conclusion- AML patients with NPM1 and FLT3 mutations have differences in clinical and hematological features, which might represent their different molecular mechanism in leukemogenesis. The frequency of NPM1 and FLT3 mutations in this study was comparable to reports from Asian countries but lower than that reported from western countries. However, as the number of patients in the study was less, a larger number of patients need to be studied to corroborate these findings.

CD4+ CD25high Regulatory T Cells in Newly Diagnosed Patients with Acute Myeloid Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2835-2835
Author(s):  
Miroslaw J. Szczepanski ◽  
Laura Strauss ◽  
Malgorzata Czystowska ◽  
Marta Szajnik ◽  
Ann Welsh ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Myeloid Leukemia ◽  
Regulatory T Cells ◽  
Myeloid Leukemia ◽  
Fas Ligand ◽  
Hematologic Malignancies ◽  
Newly Diagnosed ◽  
Therapeutic Implications ◽  
Healthy Donors ◽  
Acute Myeloid

Abstract Regulatory CD4+CD25+ T cells (T reg) are critical regulators of immune tolerance. Increasing evidence supports the existence of elevated numbers of regulatory T cells in cancer patients. Although the increase of T cells seems to be a characteristic feature in most tumors the functional role of Treg, especially in patients with hematologic malignancies, has been less well defined. Mutlicolor flow cytomerty was used to investigated the frequency and phenotype of CD4+ CD25high T cells in the peripheral blood of thirty seven newly diagnosed acute myeloid leukemia (AML) patients (prior to any treatment) and thirty one healthy donors. The suppressive function of Treg was evaluated using CFSE-labeled fresh autologous CD4+CD25− T cells activated with an anti-CD3 antibody as responders. The percentage of circulating CD4+ CD25high Treg was higher (p < 0.0001) in the AML patients (2.9 ± 0.3%, range 0.1–7%) compared to healthy donors (0.4 ± 0.02%, range 0.1–1%). Percentages of T reg expressing Foxp3, CTLA-4, CD45 RO, Fas ligand (CD95) and GITR were significantly elevated in the circulation of AML patients compared to healthy donors: Foxp3 60vs32% p<0.001, CTLA-4 47vs21% p<0.01, CD45 RO 81vs53% p<0.002, Fas ligand 23vs4% p<0.001, GITR 65vs25% p<0.001. Suppression mediated by T reg co-incubated with proliferating autologous responders was also significantly higher (p<0.001) in AML than that mediated by control T reg (75 ± 6% vs 12% ± 4%). These results indicate that T reg accumulate in the periphery of patients with AML and mediate vigorous suppression. Modulation of the Treg suppressive activity, especially during the post-induction period, in AML patients may have therapeutic implications.

scholarly journals MicroRNAs and acute myeloid leukemia: therapeutic implications and emerging concepts

Blood ◽  
2017 ◽  
Vol 130 (11) ◽  
pp. 1290-1301 ◽  
Author(s):  
Jared A. Wallace ◽  
Ryan M. O’Connell
Keyword(s):  
Acute Myeloid Leukemia ◽  
Messenger Rna ◽  
Myeloid Leukemia ◽  
Cellular Proliferation ◽  
Hematologic Malignancy ◽  
Noncoding Rnas ◽  
Disease Development ◽  
Therapeutic Implications ◽  
The Past ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is a deadly hematologic malignancy characterized by the uncontrolled growth of immature myeloid cells. Over the past several decades, we have learned a tremendous amount regarding the genetic aberrations that govern disease development in AML. Among these are genes that encode noncoding RNAs, including the microRNA (miRNA) family. miRNAs are evolutionarily conserved small noncoding RNAs that display important physiological effects through their posttranscriptional regulation of messenger RNA targets. Over the past decade, studies have identified miRNAs as playing a role in nearly all aspects of AML disease development, including cellular proliferation, survival, and differentiation. These observations have led to the study of miRNAs as biomarkers of disease, and efforts to therapeutically manipulate miRNAs to improve disease outcome in AML are ongoing. Although much has been learned regarding the importance of miRNAs in AML disease initiation and progression, there are many unanswered questions and emerging facets of miRNA biology that add complexity to their roles in AML. Moving forward, answers to these questions will provide a greater level of understanding of miRNA biology and critical insights into the many translational applications for these small regulatory RNAs in AML.

scholarly journals Mining Large Heterogeneous Cancer Data Sets Using Boolean Implications

2016 ◽  
Author(s):  
Subarna Sinha ◽  
David L Dill
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Random Variables ◽  
Data Sets ◽  
Causal Association ◽  
Dna Hypermethylation ◽  
Data Set ◽  
Therapeutic Implications ◽  
Cancer Data ◽  
Acute Myeloid

Boolean implications (if-then rules) provide a conceptually simple, uniform and highly scalable way to find associations between pairs of random variables. In this paper, we describe their usage in mining associations from large, heterogeneous cancer data sets. Next, we illustrate how Boolean implications were used to discover a new causal association between a mutation and aberrant DNA hypermethylation in acute myeloid leukemia as well as the therapeutic implications of this discovery. We conclude with a brief description of how Boolean implications can be extracted from a given data set.

scholarly journals Proteomics of Acute Myeloid Leukemia: Cytogenetic Risk Groups Differ Specifically in Their Proteome, Interactome and Posttranslational Protein Modifications.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1223-1223
Author(s):  
Mumtaz Y. Balkhi ◽  
Mulu Geletu ◽  
Maximilian Christopeit ◽  
Hermann M. Behre ◽  
Gerhard Behre
Keyword(s):  
Acute Myeloid Leukemia ◽  
Posttranslational Modifications ◽  
Myeloid Leukemia ◽  
Drug Targets ◽  
Risk Groups ◽  
Two Dimensional Gel Electrophoresis ◽  
Therapeutic Implications ◽  
Cytogenetic Aberrations ◽  
New Thinking ◽  
Acute Myeloid

Abstract Acute Myeloid Leukemia (AML) is characterized by specific cytogenetic aberrations which are strong determinants of prognostic outcome and therapeutic response. Because the clinical outcome in AML cytogenetic groups differs considerably, we hypothesized that cytogenetic risk groups of AML might differ specifically in their proteome, protein interaction pathways and posttranslational modifications (PTMs). Thus, we determined the proteome of 30 AML patients belonging to various cytogenetic groups based on two-dimensional gel electrophoresis and Nano LC coupled MALDI-TOF-TOF tandem mass spectrometry. We could identify substantial differences in the proteome, protein expression and peak pattern between cytogenetic risk groups of AML. The interactome analysis based on computational bioinformatics using Ingenuity analysis revealed major regulating networks: MAPK8 and MYC for complex aberrant karyotype AML, TP53 for t(8;21)-AML, TP53- MYC- PRKAC for 11q23-AML, JUN and MYC for inv(16)-AML. Most interestingly, peak explorer analysis revealed a modification of O-linked acetyl glucosamine of hnRNPH1 in AML patients with a 11q23 translocation, an acetylation of calreticulin in t(8;21) translocation AML, an increased intensity of dimethylated peptide of hnRNPA2/B1 in AML patients with translocations of t(8;21) and inv(16) in comparison to healthy bone marrow. We show for the first time that cytogenetic risk groups of AML differ specifically both in their proteome, interactome and PTMs. These findings lead to a new thinking about the pathogenesis of AML and has major therapeutic implications because PTMs are the primary drug targets.

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