Molecular Landscape of Acute Myeloid Leukemia: Prognostic and Therapeutic Implications

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.

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Molecular landscape of acute myeloid leukemia in younger adults and its clinical relevance

Blood ◽

10.1182/blood-2015-07-604496 ◽

2016 ◽

Vol 127 (1) ◽

pp. 29-41 ◽

Cited By ~ 206

Author(s):

David Grimwade ◽

Adam Ivey ◽

Brian J. P. Huntly

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Treatment Options ◽

Molecular Heterogeneity ◽

Prognostic Information ◽

Molecular Abnormalities ◽

Disease Entities ◽

Molecular Landscape ◽

Individualization Of Therapy ◽

Acute Myeloid

Abstract Recent major advances in understanding the molecular basis of acute myeloid leukemia (AML) provide a double-edged sword. Although defining the topology and key features of the molecular landscape are fundamental to development of novel treatment approaches and provide opportunities for greater individualization of therapy, confirmation of the genetic complexity presents a huge challenge to successful translation into routine clinical practice. It is now clear that many genes are recurrently mutated in AML; moreover, individual leukemias harbor multiple mutations and are potentially composed of subclones with differing mutational composition, rendering each patient’s AML genetically unique. In order to make sense of the overwhelming mutational data and capitalize on this clinically, it is important to identify (1) critical AML-defining molecular abnormalities that distinguish biological disease entities; (2) mutations, typically arising in subclones, that may influence prognosis but are unlikely to be ideal therapeutic targets; (3) mutations associated with preleukemic clones; and (4) mutations that have been robustly shown to confer independent prognostic information or are therapeutically relevant. The reward of identifying AML-defining molecular lesions present in all leukemic populations (including subclones) has been exemplified by acute promyelocytic leukemia, where successful targeting of the underlying PML-RARα oncoprotein has eliminated the need for chemotherapy for disease cure. Despite the molecular heterogeneity and recognizing that treatment options for other forms of AML are limited, this review will consider the scope for using novel molecular information to improve diagnosis, identify subsets of patients eligible for targeted therapies, refine outcome prediction, and track treatment response.

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The prognostic and functional role of microRNAs in acute myeloid leukemia

Blood ◽

10.1182/blood-2010-09-191312 ◽

2011 ◽

Vol 117 (4) ◽

pp. 1121-1129 ◽

Cited By ~ 168

Author(s):

Guido Marcucci ◽

Krzysztof Mrózek ◽

Michael D. Radmacher ◽

Ramiro Garzon ◽

Clara D. Bloomfield

Keyword(s):

Acute Myeloid Leukemia ◽

Messenger Rna ◽

Myeloid Leukemia ◽

Gene Mutations ◽

Microrna Expression ◽

Prognostic Information ◽

Altered Gene ◽

Functional Relevance ◽

Pharmacologic Agents ◽

Acute Myeloid

Abstract Expression of microRNAs, a new class of noncoding RNAs that hybridize to target messenger RNA and regulate their translation into proteins, has been recently demonstrated to be altered in acute myeloid leukemia (AML). Distinctive patterns of increased expression and/or silencing of multiple microRNAs (microRNA signatures) have been associated with specific cytogenetic and molecular subsets of AML. Changes in the expression of several microRNAs altered in AML have been shown to have functional relevance in leukemogenesis, with some microRNAs acting as oncogenes and others as tumor suppressors. Both microRNA signatures and a single microRNA (ie, miR-181a) have been shown to supply prognostic information complementing that gained from cytogenetics, gene mutations, and altered gene expression. Moreover, it has been demonstrated experimentally that antileukemic effects can be achieved by modulating microRNA expression by pharmacologic agents and/or increasing low endogenous levels of microRNAs with tumor suppressor function by synthetic microRNA oligonucleotides, or down-regulating high endogenous levels of leukemogenic microRNAs by antisense oligonucleotides (antagomirs). Therefore, it is reasonable to predict the development of novel microRNA-based therapeutic approaches in AML. We review herein results of current studies analyzing changes of microRNA expression in AML and discuss their potential biologic, diagnostic, and prognostic relevance.

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

International Journal of Hematology-Oncology and Stem Cell Research ◽

10.18502/ijhoscr.v15i1.5246 ◽

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.

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Molecular Genetics of Adult Acute Myeloid Leukemia: Prognostic and Therapeutic Implications

Journal of Clinical Oncology ◽

10.1200/jco.2010.30.2554 ◽

2011 ◽

Vol 29 (5) ◽

pp. 475-486 ◽

Cited By ~ 357

Author(s):

Guido Marcucci ◽

Torsten Haferlach ◽

Hartmut Döhner

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Prognostic Significance ◽

Gene Mutations ◽

Genetic Alterations ◽

Clinical Implications ◽

Therapeutic Implications ◽

Genome Wide ◽

Genome Wide Expression ◽

Acute Myeloid

Molecular analyses of leukemic blasts from patients with acute myeloid leukemia (AML) have revealed a striking heterogeneity with regard to the presence of acquired gene mutations and changes in gene and microRNA expression. Multiple submicroscopic genetic alterations with prognostic significance have been discovered. Application of gene- and microRNA profiling has identified genome-wide expression signatures that separate cytogenetic and molecular subsets of patients with AML into previously unrecognized biologic and/or prognostic subgroups. These and similar future findings are likely to have a major impact on the clinical management of AML because many of the identified genetic alterations not only represent independent prognosticators, but also may constitute targets for specific therapeutic intervention. In this report, we review genetic findings in AML and discuss their clinical implications.

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Role of FLT3 gene mutations in acute myeloid leukemia: effect on course of disease and results of therapy

Genes and Cells ◽

10.23868/201903007 ◽

2019 ◽

Vol XIV (1) ◽

Author(s):

A.M. Radzhabova ◽

S.V. Voloshin ◽

I.S. Martynkevich ◽

A.A. Kuzyaeva ◽

V.A. Shuvaev ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Gene Mutations ◽

Course Of Disease ◽

Acute Myeloid

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Next-generation sequencing reveals gene mutations landscape and clonal evolution in patients with acute myeloid leukemia

Hematology ◽

10.1080/16078454.2020.1858610 ◽

2021 ◽

Vol 26 (1) ◽

pp. 111-122

Author(s):

Xiao Chen ◽

Han Zhu ◽

Chun Qiao ◽

Sishu Zhao ◽

Lu Liu ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Next Generation Sequencing ◽

Myeloid Leukemia ◽

Clonal Evolution ◽

Gene Mutations ◽

Next Generation ◽

Generation Sequencing ◽

Acute Myeloid

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

Expert Opinion on Therapeutic Targets ◽

10.1080/14728222.2021.1915991 ◽

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

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Nanopore Targeted Sequencing for Rapid Gene Mutations Detection in Acute Myeloid Leukemia

Genes ◽

10.3390/genes10121026 ◽

2019 ◽

Vol 10 (12) ◽

pp. 1026 ◽

Cited By ~ 6

Author(s):

Cumbo ◽

Minervini ◽

Orsini ◽

Anelli ◽

Zagaria ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Low Cost ◽

Gene Mutations ◽

Predictive Biomarkers ◽

Molecular Testing ◽

Sequencing Analysis ◽

Cebpa Mutations ◽

Targeted Gene Sequencing ◽

Acute Myeloid

Acute myeloid leukemia (AML) clinical settings cannot do without molecular testing to confirm or rule out predictive biomarkers for prognostic stratification, in order to initiate or withhold targeted therapy. Next generation sequencing offers the advantage of the simultaneous investigation of numerous genes, but these methods remain expensive and time consuming. In this context, we present a nanopore-based assay for rapid (24 h) sequencing of six genes (NPM1, FLT3, CEBPA, TP53, IDH1 and IDH2) that are recurrently mutated in AML. The study included 22 AML patients at diagnosis; all data were compared with the results of S5 sequencing, and discordant variants were validated by Sanger sequencing. Nanopore approach showed substantial advantages in terms of speed and low cost. Furthermore, the ability to generate long reads allows a more accurate detection of longer FLT3 internal tandem duplications and phasing double CEBPA mutations. In conclusion, we propose a cheap, rapid workflow that can potentially enable all basic molecular biology laboratories to perform detailed targeted gene sequencing analysis in AML patients, in order to define their prognosis and the appropriate treatment.

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