Epigenetic regulation of leukemia and normal blood development - Andreas Lennartsson

We are identifying key mechanisms that cause epigenetic and transcriptional perturbation in AML in order to be able to find new ways to treat the disease.

microscopy image of enrichment of cells
AML is characterized by an abnormal enrichment of immature blood progenitor cells that have lost their potential to differentiate to mature blood cells. Photo: https://stock.adobe.com/se/ License to Andreas Lennartsson

Acute myeloid leukaemia (AML) has a poor prognosis in both, adults and children. There is therefore an urgent need for new novel therapeutics.Dramatic improvements in treatment and outcome have been made,when the biology is wellcharacterised. For acute promyelocytic leukaemia (APML) the long-term survival nowexceeds 90%, demonstrating that a better understanding of AML biology is a pre-requisite for the development of novel therapies to improve treatment outcomes. AML ischaracterised by early mutations and chromosomal aberrations in epigenetic regulators and transcription factors. Therefore, we are focusing our research on epigenetic regulation and epigenetic treatment of AML.

graphic illustration of tumours and genes
Disturbed epigenetic regulation in AML can lead to silencing of tumour suppressor genes and development and maintenance of AML. Illustration: by deusin https://stock.adobe.com/se/ License to Andreas Lennartsson

We are using cutting edge genome-wide technologies, biochemistry and molecular biology methods, novel model-systems and primary patient material, to obtain an increased knowledge of the molecular mechanisms thatdrive AML. The results are used to identify new drugs and drug combinations to develop improved treatments for AML. We are working together with several international research groupswho are developing technologies to be able to analyse transcriptomics and epigenomics in new ways and in small cell populations, such as the leukemic stem cells. In addition, we have close collaborations with clinical haematologists to be able to ask the clinically important research questions. Within this network of technical knowhow, clinical expertise and scientific drive, we have the tools to make major advances in the treatment of AML.

Our projects include:

  • Epigenetic regulations of normal blood development, to better understand the perturbations found in AML
  • Identifying epigenetic disturbance in AML patients.
  • Using iPS cells retrieved from AML patients as a model system to understand the molecular development of AML.
  • Testing and analysing thedrug response of novel drug or drug combinations, both in vitro and by participating in clinical trials.

Group members

Sophia Miliara

Postdoctoral researcher

Anna Palau De Miguel

Postdoctoral researcher

Xiangfu Zhong

Bioinformatician
group photo of some people standing in a snowy landscape
Group photo, Andreas Lennartsson's group, from the left: Farzaneh Varnoosfaderani Shahin, Wenbo Dong, Sophia Miliara, Anna Palau and Andreas Lennartsson.

Looking for a Postdoc or Master position?

We are always interested to recruit motivated students and postdocs!

Please contact Andreas Lennartsson for more information.

 

Selected publications

AML Displays Increased CTCF Occupancy Associated to Aberrant Gene Expression and Transcription Factor Binding
Huthayfa Mujahed, Sophia Miliara, Anne Neddermeyer , Sofia Bengtzén, Christer Nilsson, Stefan Deneberg, Lina Cordeddu, Karl Ekwall, Andreas Lennartsson*, Sören Lehmann*
* shared last author
Blood, 2020 in press

A regulatory role for CHD2 in myelopoiesis.
Shahin Varnoosfaderani F, Palau A, Dong W, Persson J, Durand-Dubief M, Svensson JP, Lennartsson A.
Epigenetics. 2020 Jan 10:1-13. doi: 10.1080/15592294.2019.1710913

Depletion of the transcriptional coactivators CREB-binding protein or EP300 downregulates CD20 in diffuse large B-cell lymphoma cells and impairs the cytotoxic effects of anti-CD20 antibodies.
Scialdone A, Khazaei S, Hasni MS, Lennartsson A, Gullberg U, Drott K
Exp. Hematol. 2019 11;79():35-46.e1

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