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Epigenetic regulation of acute myeloid leukemia - Andreas Lennartsson

Acute myeloid leukemia (AML) has a poor prognosis in both, adults and children, with a long-term survival of only 15% and 50% respectively.

The mainstay of treatment, standard combination chemotherapy, appears to have reached the limit of its impact. There is therefore an urgent need for new novel therapeutics in childhood and adult acute leukemia’s. Improvements have been dramatic when the biology is well characterized, such as in the acute promyelocytic leukemia (APML) subtype, with cure rates now exceeding 90% for this subtype. These data demonstrate that a better understanding of AML biology is a pre-requisite for the development of novel therapies to improve treatment outcomes.

We and others have demonstrated that the generation of tissue-specific patterns of gene expression involves the interplay of combinatorial patterns of specific enhancer elements with their cognate promoters. We predict that the normal epigenetic remodeling of enhancers, which are required to generate specialized transcriptional programs that are necessary for hematopoietic development, is corrupted during the evolution of leukemia. Although we know that transcription is altered and drives the leukemic phenotype in the majority of AML cases, the mechanisms that initiate and maintain these aberrant transcriptional programs are poorly understood. Details of transcriptional alterations, the mechanisms involved and how these might be therapeutically targeted, will help us to identify novel therapeutic targets and therapies.

The relapse and consequently the poor prognosis of AML patients are often caused by leukemic stem cells. AML is associated with perturbed epigenetic regulation, with both mutations in and chromosomal rearrangements of epigenetic factors. Therefore, the aim of this project is to investigate the regulatory epigenetic molecular mechanisms of leukemic stem cells.

Our specific aims are to:

  1. Map how the epigenetic modifications that are connected to enhancers are disturbed in acute myeloid leukemic stem cells.
  2. Characterize the effect the deregulated epigenetic modifications have on enhancer activity and on the transcriptional program that creates and stabilize multi-potency.
  3. Identify key epigenetic factors that regulate enhancer activity and multi-potency in hematopoietic stem cells.
  4. Investigate whether these epigenetic factors are deregulated in AML and how they contribute to the leukemic phenotype.
  5. Analyze the role of the identified epigenetic factors have in drug resistance.

Team members

 

Selected publications

Polycomb protein RING1A limits hematopoietic differentiation in myelodysplastic syndromes.
Palau A, Garz AK, Diesch J, Zwick A, Malinverni R, Valero V, et al
Oncotarget 2017 Dec;8(70):115002-115017

Cancer-specific changes in DNA methylation reveal aberrant silencing and activation of enhancers in leukemia.
Qu Y, Siggens L, Cordeddu L, Gaidzik VI, Karlsson K, Bullinger L, et al
Blood 2017 02;129(7):e13-e25

Major transcriptional changes observed in the Fulani, an ethnic group less susceptible to malaria.
Quin JE, Bujila I, Chérif M, Sanou GS, Qu Y, Vafa Homann M, et al
Elife 2017 09;6():

The transcriptional coregulator NAB2 is a target gene for the Wilms' tumor gene 1 protein (WT1) in leukemic cells.
Nilsson HJ, Montano G, Ullmark T, Lennartsson A, Drott K, Järvstråt L, et al
Oncotarget 2017 Oct;8(50):87136-87150

FANTOM5 CAGE profiles of human and mouse samples.
Noguchi S, Arakawa T, Fukuda S, Furuno M, Hasegawa A, Hori F, et al
Sci Data 2017 08;4():170112

Comprehensive mapping of the effects of azacitidine on DNA methylation, repressive/permissive histone marks and gene expression in primary cells from patients with MDS and MDS-related disease.
Tobiasson M, Abdulkadir H, Lennartsson A, Katayama S, Marabita F, De Paepe A, et al
Oncotarget 2017 Apr;8(17):28812-28825

The HDAC inhibitor valproate induces a bivalent status of the CD20 promoter in CLL patients suggesting distinct epigenetic regulation of CD20 expression in CLL in vivo.
Scialdone A, Hasni MS, Damm JK, Lennartsson A, Gullberg U, Drott K
Oncotarget 2017 Jun;8(23):37409-37422

Update of the FANTOM web resource: high resolution transcriptome of diverse cell types in mammals.
Lizio M, Harshbarger J, Abugessaisa I, Noguchi S, Kondo A, Severin J, et al
Nucleic Acids Res. 2017 01;45(D1):D737-D743

Distinct global binding patterns of the Wilms tumor gene 1 (WT1) -KTS and +KTS isoforms in leukemic cells.
Ullmark T, Järvstråt L, Sandén C, Montano G, Jernmark-Nilsson H, Lilljebjörn H, et al
Haematologica 2017 02;102(2):336-345

Mutations in histone modulators are associated with prolonged survival during azacitidine therapy.
Tobiasson M, McLornan DP, Karimi M, Dimitriou M, Jansson M, Ben Azenkoud A, et al
Oncotarget 2016 Apr;7(16):22103-15

Remodeling of retrotransposon elements during epigenetic induction of adult visual cortical plasticity by HDAC inhibitors.
Lennartsson A, Arner E, Fagiolini M, Saxena A, Andersson R, Takahashi H, et al
Epigenetics Chromatin 2015 ;8():55

Transcription-coupled recruitment of human CHD1 and CHD2 influences chromatin accessibility and histone H3 and H3.3 occupancy at active chromatin regions.
Siggens L, Cordeddu L, Rönnerblad M, Lennartsson A, Ekwall K
Epigenetics Chromatin 2015 ;8(1):4

EpiFactors: a comprehensive database of human epigenetic factors and complexes.
Medvedeva YA, Lennartsson A, Ehsani R, Kulakovskiy IV, Vorontsov IE, Panahandeh P, et al
Database (Oxford) 2015 ;2015():bav067

Technical Advance: Transcription factor, promoter, and enhancer utilization in human myeloid cells.
Joshi A, Pooley C, Freeman TC, Lennartsson A, Babina M, Schmidl C, et al
J. Leukoc. Biol. 2015 May;97(5):985-995

Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells.
Arner E, Daub CO, Vitting-Seerup K, Andersson R, Lilje B, Drabløs F, et al
Science 2015 Feb;347(6225):1010-4

microRNA-34b/c on chromosome 11q23 is aberrantly methylated in chronic lymphocytic leukemia.
Deneberg S, Kanduri M, Ali D, Bengtzen S, Karimi M, Qu Y, et al
Epigenetics 2014 Jun;9(6):910-7

Analysis of the DNA methylome and transcriptome in granulopoiesis reveals timed changes and dynamic enhancer methylation.
Rönnerblad M, Andersson R, Olofsson T, Douagi I, Karimi M, Lehmann S, et al
Blood 2014 Apr;123(17):e79-89

High-throughput transcription profiling identifies putative epigenetic regulators of hematopoiesis.
Prasad P, Rönnerblad M, Arner E, Itoh M, Kawaji H, Lassmann T, et al
Blood 2014 Apr;123(17):e46-57

The DEK oncoprotein binds to highly and ubiquitously expressed genes with a dual role in their transcriptional regulation.
Sandén C, Järvstråt L, Lennartsson A, Brattås PL, Nilsson B, Gullberg U
Mol. Cancer 2014 Sep;13():215

Differential methylation in CN-AML preferentially targets non-CGI regions and is dictated by DNMT3A mutational status and associated with predominant hypomethylation of HOX genes.
Qu Y, Lennartsson A, Gaidzik VI, Deneberg S, Karimi M, Bengtzén S, et al
Epigenetics 2014 Aug;9(8):1108-19

A promoter-level mammalian expression atlas.
, Forrest AR, Kawaji H, Rehli M, Baillie JK, de Hoon MJ, et al
Nature 2014 Mar;507(7493):462-70

An atlas of active enhancers across human cell types and tissues.
Andersson R, Gebhard C, Miguel-Escalada I, Hoof I, Bornholdt J, Boyd M, et al
Nature 2014 Mar;507(7493):455-461

Forced expression of the DEK-NUP214 fusion protein promotes proliferation dependent on upregulation of mTOR.
Sandén C, Ageberg M, Petersson J, Lennartsson A, Gullberg U
BMC Cancer 2013 Sep;13():440

Leukemia associated mutant Wilms' tumor gene 1 protein promotes expansion of human hematopoietic progenitor cells.
Vidovic K, Ullmark T, Rosberg B, Lennartsson A, Olofsson T, Nilsson B, et al
Leuk. Res. 2013 Oct;37(10):1341-9

Allele-specific programming of Npy and epigenetic effects of physical activity in a genetic model of depression.
Melas PA, Lennartsson A, Vakifahmetoglu-Norberg H, Wei Y, Åberg E, Werme M, et al
Transl Psychiatry 2013 May;3():e255

Antidepressant treatment is associated with epigenetic alterations in the promoter of P11 in a genetic model of depression.
Melas PA, Rogdaki M, Lennartsson A, Björk K, Qi H, Witasp A, et al
Int. J. Neuropsychopharmacol. 2012 Jun;15(5):669-79

Prognostic DNA methylation patterns in cytogenetically normal acute myeloid leukemia are predefined by stem cell chromatin marks.
Deneberg S, Guardiola P, Lennartsson A, Qu Y, Gaidzik V, Blanchet O, et al
Blood 2011 Nov;118(20):5573-82

Wilms' tumor gene 1 protein represses the expression of the tumor suppressor interferon regulatory factor 8 in human hematopoietic progenitors and in leukemic cells.
Vidovic K, Svensson E, Nilsson B, Thuresson B, Olofsson T, Lennartsson A, et al
Leukemia 2010 May;24(5):992-1000

The transcriptional network that controls growth arrest and differentiation in a human myeloid leukemia cell line.
, Suzuki H, Forrest AR, van Nimwegen E, Daub CO, Balwierz PJ, et al
Nat. Genet. 2009 May;41(5):553-62

External signals shape the epigenome.
Lennartsson A
Genome Biol. 2016 Feb;17():18

Epigenetic aberrations in acute myeloid leukemia: Early key events during leukemogenesis.
Eriksson A, Lennartsson A, Lehmann S
Exp. Hematol. 2015 Aug;43(8):609-24

The roles of SNF2/SWI2 nucleosome remodeling enzymes in blood cell differentiation and leukemia.
Prasad P, Lennartsson A, Ekwall K
Biomed Res Int 2015 ;2015():347571

Histone modification patterns and epigenetic codes.
Lennartsson A, Ekwall K
Biochim. Biophys. Acta 2009 Sep;1790(9):863-8

 

Book chapters

Dynamics and Function of DNA Methylation During Development
A Lennartsson
Chromatin Regulation and Dynamics, Translational Epigenetics series, Elsevier 2016

Editorials

Epigenetic alterations related to early life stressful events
Lennartsson A
Acta Neuropsychiatrica 2012: 24: 253–254
http://onlinelibrary.wiley.com/doi/10.1111/acn.12012/abstract