Molecular Landscape of Acute Myeloid Leukemia: Prognostic and Therapeutic Implications.

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. 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

Independence of epigenetic and genetic diversity in AML.

A new study provides the first insights into epigenetic heterogeneity in AML. The study highlights a striking independence of genetic and epigenetic variation, and links the kinetics of epigenetic change to clinical outcome.Medical Research Council, Wellcome Trust, Mildred-Scheel OrganisationThis is the author accepted manuscript. The final version is available from Nature Publishing Group via http://dx.doi.org/10.1038/nm.413

Histone modifiers are oxygen sensors.

Hypoxia signals directly to chromatin via histone demethylases to alter gene expression</jats:p

Prognostic models turn the Heat(IT)up on FLT3ITD-mutated AML.

The presence of internal tandem duplications (ITDs) in the FLT3 receptor tyrosine kinase gene have long been known to confer a poor prognosis to acute myeloid leukemia (AML) patients. Now, specific structural features of the ITD are also suggested to alter patient outcome, including sensitivity to targeted therapies, prompting their evaluation in therapeutic algorithms.B.J.P. Huntly is supported by The European Research Council (COMAL: 647685) and Cancer Research UK (A25508). P. Gallipoli is supported by the Wellcome Trust (109967/Z/15/Z) and an ASH Global Research Award

Acute myeloid leukemia: leukemia stem cells write a prognostic signature

In a recent interesting article, analysis of gene expression between phenotypically defined acute myeloid leukemia (AML) leukemia stem cells (LSCs) and more mature leukemia progenitor cells is used to generate a differentially expressed gene signature for LSCs. Through clever bioinformatic weighting analysis, the authors describe a method to convert this signature into a single score for any given sample and then test the prognostic utility of this 'LSC score' in publicly available gene expression profiles from bulk AML samples. They demonstrate that a high LSC score is associated with poor prognosis in AML patients and further demonstrate that the score is independent of known prognostic factors, including age, karyotype and mutation of the FLT3 or NPM1 genes. These findings are important and directly relate transcriptional dysregulation in AML LSCs with the outcome in patient samples, thus reinforcing the belief that these cellular populations are crucial for the initial propagation and subsequent relapse and resistance of leukemia

Epigenetic regulators as promising therapeutic targets in acute myeloid leukemia.

Acute myeloid leukemia (AML), the most prevalent acute leukemia in adults, is an aggressive hematological malignancy arising in hematopoietic stem and progenitor cells. With the exception of a few specific AML subtypes, the mainstays of treatment have not significantly changed over the last 20 years, and are still based on standard cytotoxic chemotherapy. As a result, clinical outcome remains poor for the majority of patients, with overall long-term survival in the region of 20-30%. Recent successes in characterizing the genetic landscape of AML have highlighted that, despite its heterogeneity, many cases of AML carry recurrent mutations in genes encoding epigenetic regulators. Transcriptional dysregulation and altered epigenetic function have therefore emerged as exciting areas in AML research and it is becoming increasingly clear that epigenetic dysfunction is central to leukemogenesis in AML. This has subsequently paved the way for the development of epigenetically targeted therapies. In this review, we will discuss the most recent advances in our understanding of the role of epigenetic dysregulation in AML pathobiology. We will particularly focus on those altered epigenetic programs that have been shown to be central to the development and maintenance of AML in preclinical models. We will discuss the recent development of therapeutics specifically targeting these key epigenetic programs in AML, describe their mechanism of action and present their current clinical development. Finally, we will discuss the opportunities presented by epigenetically targeted therapy in AML and will highlight future challenges ahead for the AML community, to ensure that these novel therapeutics are optimally translated into clinical practice and result in clinical improvement for AML patients.We would like to thank all the members of the Huntly laboratory and our funders Leukaemia Lymphoma Research, Kay Kendall Leukaemia fund, the Medical Research Council UK, the Wellcome Trust, the Cambridge NIHR Biomedical Research Centre, Leukemia & Lymphoma Society US, the Academy of Medical Sciences UK and Lady Tata Memorial Trust. We apologise to writers whose work we have failed to cite due to space constraints.This is the author accepted manuscript. The final version is available via SAGE at http://dx.doi.org/10.1177/204062071557761

Hematopoietic stem cells made BETter by inhibition.

Bromodomain and extra terminal (BET) proteins comprise the ubiquitously expressed BRD2, BRD3, BRD4 and the testes specific BRDT. These multipurpose proteins contain tandem N-terminal bromodomains that bind acetylated lysine residues of histone (and non-histone) proteins and other protein modules, such as the extra terminal domain, and in some (BRD4, BRDT), a C-terminal domain. They also mediate a number of effects including transcriptional activation via recruitment of other partner proteins. Inhibitors of these proteins are emerging as exciting new therapies for the treatment of hematologic and solid malignancies, offering the possibility of specifically targeting epigenetic readers. We and others have already demonstrated the preclinical efficacy of BET inhibitors in acute myeloid leukemia (AML), while several other papers have documented similar efficacy in myeloma, non-Hodgkin lymphoma, and acute lymphoblastic leukemia. These observations have led to several clinical trials that are currently underway to confirm the efficacy of these drugs in AML and other malignancies. Even though the most mature trials have recently reported limited objective responses of monotherapy in heavily pre-treated AML, lymphoma and myeloma patients, early data suggest that combination therapies with other small molecules or more conventional cytotoxic agents might be particularly promising

Molecular Landscape of Acute Myeloid Leukemia: Prognostic and Therapeutic Implications

Funder: University of CambridgeAbstract: 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

Molecular Landscape of Acute Myeloid Leukemia: Prognostic and Therapeutic Implications

Funder: University of CambridgeAbstract: 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