Breaking the LSD1/KDM1A Addiction: Therapeutic Targeting of the Epigenetic Modifier in AML

Lokken, Alyson A.; Zeleznik‐Le, Nancy J.

doi:10.1016/j.ccr.2012.03.027

Cited by 52 publications

(48 citation statements)

References 10 publications

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“…These effects correlated with global changes in DNA methylation/histone state and suggest the induction of differentiation through alterations in the epigenetic state of mutant cells as a putative mechanism of action for these compounds [Kernytsky et al 2014]. [Shi et al 2005], lysine specific demethylase 1 (LSD1) has emerged as a promising therapeutic target in multiple cancers, notably in AML [Berglund et al 2008;Lokken and Zeleznik-Le, 2012;Schenk et al 2012;Fiskus et al 2014c;Niebel et al 2014]. Its main role is demethylation of H3K4me1/2 and H3K9me1/2 (although it can also demethylate nonhistone proteins such as DNMT1 and TP53) and LSD1 has been shown to dynamically affect a wide range of transcriptional programs in a contextspecific manner, acting either as a transcriptional repressor or activator [Metzger et al 2005;Wang et al 2007Wang et al , 2009Cai et al 2011;Huang et al 2007;Kerenyi et al 2013].…”

Section: Epigenetic Regulators As Promising Therapeutic Targets In Acmentioning

confidence: 99%

Epigenetic regulators as promising therapeutic targets in acute myeloid leukemia

Gallipoli

Giotopoulos

Huntly

2015

Therapeutic Advances in Hematology

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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.

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Section: Epigenetic Regulators As Promising Therapeutic Targets In Acmentioning

confidence: 99%

Epigenetic regulators as promising therapeutic targets in acute myeloid leukemia

Gallipoli

Giotopoulos

Huntly

2015

Therapeutic Advances in Hematology

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“…Moreover, the speculation that the LSD1 inhibition suppress DNMT3A activity is supported by fluorescence polarization and isothermal titration calorimetry experiments [52,65] Work by Petell and coworkers shows that LSD1-facilitated interaction of Dnmt3a with histone tails, which is reduced by LSD1 inhibitor treatment [11]. An innovative approach could interfere effectively without blocking the target enzymatic activity by using peptide against specific region of the two enzymes to provide novel, specific, low-toxicity treatment agents to supplement current reatment protocols [66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84]. …”

Section: Resultsmentioning

confidence: 99%

Biology of DNMT3 and LSD1 inhibition in acute myeloid leukaemia (AML)

Messina¹

2017

Hematol Med Oncol

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Epigenetic dysregulation plays a critical role in the pathogenesis of acute myeloid leukaemia (AML). The enzymes DNA methyl-transferase (DNMT3a) and Histone Lysine Demethylase (LSD1 or KDM1) are key molecules involved in transcription, DNA repair and differentiation of myeloid cells. In fact, DNMT3a is one of the most frequently mutated genes in acute myeloid leukaemia (AML) and LSD1 is essential in retinoic acid induced differentiation of myeloid cells. However, despite extensive investigation, it is not yet known their precise role in the evolution of AML clones. This information may be relevant for the successful management of the disease. In fact, it is unclear whether, mutated DNMT3a in AML clones has a dominant negative function and disrupts the formation of transcriptional complexes leading to aberrant methylation. Also, it is not known how LSD1 inhibition impacts on growth, differentiation and chemo-resistance of leukemic myeloid cells. In this review, we focus on the emerging evidences that correlate LSD1 and DNMT3a activity in acute myeloid leukaemia, their clinical relevance and how a deeper understanding of their biological function could lead to the discovery of new specific targets, some of which are currently tested in mechanism-based clinical trials.

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“…Targets of LSD1 include H3K4 and H3K9, and its effects on these two critical substrates give it a central role in transcriptional regulation. LSD1 is highly expressed in AML [5, 39], suggesting that it could function as an oncogene, thereby representing a potential therapeutic target. Several recent studies identified a role for LSD1 in acute leukemia, as well as suggesting that LSD1 inhibitors could be useful in its treatment [29, 39, 61].…”

Section: Protein Methylationmentioning

confidence: 99%

Histone-modifying enzymes: their role in the pathogenesis of acute leukemia and their therapeutic potential

Luciani

Nimer

2013

Int J Hematol

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Histone-modifying enzymes have recently been shown to play a central role in the regulation of both normal and malignant hematopoiesis. Post-translational modifications of histones and non-histone proteins underlies a regulatory complexity affecting numerous processes including transcriptional regulation, RNA processing and DNA damage response. Insights into the functions of these enzymes as well as their role in the epigenetic alterations found in leukemia will guide the development of novel therapeutic approaches. This review discusses examples of the proteins that have been implicated in the pathogenesis of leukemia, that may serve as potential therapeutic targets.

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Breaking the LSD1/KDM1A Addiction: Therapeutic Targeting of the Epigenetic Modifier in AML

Cited by 52 publications

References 10 publications

Epigenetic regulators as promising therapeutic targets in acute myeloid leukemia

Epigenetic regulators as promising therapeutic targets in acute myeloid leukemia

Biology of DNMT3 and LSD1 inhibition in acute myeloid leukaemia (AML)

Histone-modifying enzymes: their role in the pathogenesis of acute leukemia and their therapeutic potential

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