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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

Group Leader, PhD, Associate Professor

Andreas Lennartsson

Telefon: +46 (0) 8-524 811 54
E-post: andreas.lennartsson@ki.se

I did my PhD in Experimental hematology at Lund University, Sweden. After my PhD I continued to the OMICS center at RIKEN in Japan for post-doc training in Piero Carninci's group and then to Karl Ekwall's group at Karolinska Institute for my second postdoc.


PhD, Postdoc

Anna Palau de Miguel

E-post: anna.palau.de.miguel@ki.se

I obtained my Bachelor’s degree in Pharmaceutical Sciences, from the University of Barcelona and Master’s degree in Biomedical Research from the University Pompeu Fabra (Barcelona). In 2016, I completed my PhD studies in Marcus Buschbeck's group at the Josep Carreras Leukaemia Research Institute (Barcelona).


Postdoc

Sophia Miliara

Enhet: Institutionen för biovetenskaper och näringslära (BioNut), H2
E-post: sophia.miliara@ki.se

PhD student

Farzaneh Shahin Varnoosfaderani

E-post: farzaneh.shahin.varnoosfaderani@ki.se

She was awarded a Master of Science in Biochemistry at Tarbiat Modares University, Tehran, Iran, in 2010.


Forskarstuderande

Wenbo Dong

Enhet: Lennartsson
E-post: wenbo.dong@ki.se

Financial support

Barncancerfonden
Cancerfonden
Radiumhemmets forskningsfonder
Vetenskapsrådet
Dr Åke Olssons stiftelse

Selected publications

29383137

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27612989

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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