Medicine in focus
Acute myeloid leukemia: Therapeutic impact of epigenetic drugs

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Abstract

Acute myeloid leukemia (AML) is not a single disease but a group of malignancies in which the clonal expansion of various types of hematopoietic precursor cells in the bone marrow leads to perturbation of the delicate balance between self-renewal and differentiation that is characteristic of normal hematopoiesis. An increasing number of genetic aberrations, such as chromosomal translocations that alter the function of transcription regulatory factors, has been identified as the cause of AML and shown to act by deregulating gene programming at both the genetic and epigenetic level. While the genetic aberrations occurring in acute myeloid leukemia are fairly well understood, we have only recently become aware of the epigenetic deregulation associated with leukemia, in particular with myeloid leukemias. The deposition of epigenetic “marks” on chromatin – post-translational modifications of nucleosomal proteins and methylation of particular DNA sequences – is accomplished by enzymes, which are often embedded in multi-subunit “machineries” that have acquired aberrant functionalities during leukemogenesis. These enzymes are targets for so-called “epi-drugs”. Indeed, recent results indicate that epi-drugs may constitute an entirely novel type of anti-cancer drugs with unanticipated potential. Proof-of-principle comes from studies with histone deacetylase inhibitors, promising novel anti-cancer drugs. In this review we focus on the epigenetic mechanisms associated with acute myeloid leukemogenesis and discuss the therapeutic potential of epigenetic modulators such as histone deacetylase and DNA methyltransferase inhibitors.

Introduction

Leukemia is the manifestation of the inappropriate expansion of hematopoietic progenitor cells, often due to a block of cell maturation at early stages in the cell lineages that give rise to the various cell types that constitute normal blood. Through recurrent specific genetic aberrations, such as chromosome breaks, rearrangements that transfer genes into distinct genetic contexts or generate fusion proteins with altered functionalities, genes have been identified whose altered functionality was critically or causally linked to leukemogenesis. In particular, acute myeloid leukemia (AML) is a malignant tumour of hematopoietic precursor cells of non-lymphoid lineage, with an annual incidence of 1/10,000 and a frequency that increases with age (Table 1). While AMLs were previously sub-divided following the French–American–British (FAB) classification according to blast morphology, immunophenotype, cytogenetics and clinical features, the WHO classification incorporates in addition to those parameters more recent discoveries regarding the genetics and clinical features of AML in an attempt to define entities that are biologically homogeneous and that have prognostic and therapeutic relevance (WHO; Table 2). The most studied AML subtype is acute promyelocytic leukemia (APL; FAB M3) of which more than 90% display the chromosomal translocation t(15;17) that generates the PML–RARα fusion protein comprising parts of the PML and retinoic acid receptor alpha (RARα) genes. In the past years, the functions that have been altered by the presence of different oncogenic fusion proteins such as PML–RARα in APL or AML–ETO in some AML are increasingly well understood. However, only recently, we have begun to unravel the epigenetic (and thus in principle, reversible) phenomena that contribute, together with genetic aberrations, to the development of leukemia, and malignancies in general, by the recognition and dissection of multi-subunit chromatin-modifying machineries. Epigenetic phenomena refer to ‘mitotically and meiotically heritable changes in gene expression that are not coded in the DNA sequence itself’ (Egger, Liang, Aparicio, & Jones, 2004). But often the term ‘epigenetic’ is in general applied to describe events originated from the post-translational modification of the main chromatin components, histones and DNA, or even transcription factors. Moreover, an ‘histone code’ hypothesis has been formulated (Strahl & Allis, 2000) to propose that the panel of modifications such as acetylation, methylation, phosphorylation, ubiquitination, sumoylation or ADP ribosylation deposit epigenetically relevant information at defined genetic loci to regulate most, if not all, chromatin-templated processes (see Fig. 1 for epigenetic modifications of the histone tails). Theoretically, the complexity of such a ‘histone code’ would by far exceed that of the classical genetic code. However, an alternative view is that histone modifications may just correspond to steps in a complex signalling process (Kurdistani, Tavazoie, & Grunstein, 2004). Importantly, modifications of the DNA and histone modification patterns have both been associated with cancer and epigenetic deregulations are increasingly recognized as mechanisms exploited by tumors to silence gene programs that regulate growth, DNA repair and apoptosis (Ayton, Chen, & Cleary, 2004; Egger et al., 2004, Esteller, 2005; Feinberg & Tycko, 2004; Laird, 2003, Villa et al., 2004). Notably, in contrast to genetic modifications, epigenetic alterations are transient and can be reversed, at least partially, by treatment with epigenetic drugs (Brueckner & Lyko, 2004; Somech, Izraeli, & Simon, 2004). Pioneering work has unraveled the link between oncogenic fusion proteins (such as PML–RARα, PLZF–RARα, AML–ETO, etc.) – that cause acute myeloid leukaemia – with the aberrant recruitment of histone deacetylases and DNA methyltransferase, enzymes involved in gene silencing. Various types of inhibitors (HDAC-Is and DNMT-Is) have been generated and we are now witnessing the elucidation of structure–activity relationships of HDAC-Is (Marks, Richon, Miller, & Kelly, 2004) and the mechanism(s) of their anti-cancer action (Insinga et al., 2005, Nebbioso et al., 2005). Moreover, therapies are being explored in which two epigenetic (e.g. an HDAC and a DNA methyltransferase inhibitor) drugs or an epigenetic and a signalling drug (e.g. HDAC-I and retinoic acid) are combined to specify action, decrease effective concentration due to drug synergy and thus, reduce side effects.

Section snippets

Genetic aberrations causing acute myeloid leukemia affect epigenetic gene regulation

Acute myeloid leukemia (AML), the collective description of a variety of myeloid leukemias characterized by a block of differentiation at various early stages in the myeloid lineage, is frequently associated with the common karyotype abnormalities that affect a number of specific genes believed to regulate critical steps in normal myelopoiesis. Common abnormalities cluster often, but not always, with common AML subtypes. In some cases, such as the t(15;17) translocation generating the PML–RARα

Differentiation therapy of myeloid leukaemia

Cancer ‘differentiation therapy’ refers to a novel type of treatment by which a (signaling, epigenetic) drug forces a tumor cell to adapt a more, preferentially terminally, differentiated state that leads to apoptosis. Such drugs do not necessarily display the toxicity commonly associated with chemotherapy. Presently, several compounds are in clinical use but the most successful example of differentiation therapy is APL with the use of all-trans retinoic acid which combined with chemotherapy

Coming of age: Epigenetic therapy of leukemia

Solid evidence demonstrates that in addition to genetic alteration, aberrant epigenetic regulation, such as silencing of tumor suppressors, is used by cancer cells to escape growth and death control mechanisms (for review and references see Esteller, 2005). Thus, compounds able to influence the epigenetic status of a cell have promise for cancer treatment. DNMT-Is have been already largely tested in cancers. One of the most recent results obtained 30–60% response rates in leukemias (Issa et

Conclusions and perspectives

The progresses on the functional characterization of DNMTs and HDACs will enable a more rational approach to drug design. Targeted design of epigenetic modulators together with the development of molecular models for screening purposes will facilitate the identification of more specific and selective molecules. Furthermore, defining the action spectra of HDACs, using genetics, antisense oligonucleotides, siRNAs and inhibitors, will provide the basis for targeted clinical use of potentially very

Acknowledgements

Supported by the European Community (QLG1-CT-2000-01935 and QLK3-CT-2002-02029), the Institut Nationale de la Santè et de la Recherche Médicale, the Centre National de La Recherche Scientifique, the Hòpital Universitaire de Strasbourg, the Association for International Cancer Research, the Association pour la Recherche sur le Cancer, the Fondation de France, the Regione Campania Legge 5/2002, PRIN 2004-055579, the Ministero dell Salute R.F.02/184, the French-Italian GALILEO project.

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