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.
Acute myeloid leukaemia (AML) has a poor prognosis in both, adults and children. Acute leukemia accounts for 30% of the diagnosed cases of pediatric cancer. Acute lymphoblastic leukemia (ALL) is the most common subtype in children and has good prognosis with 80-90% survival. However, pediatric and infant acute myeloid leukemia still have a poor outcome. There is therefore an urgent need for new novel therapeutics. Dramatic improvements in treatment and outcome have been made, when the biology is well-characterised. For acute promyelocytic leukaemia (APML) the long-term survival now exceeds 90%, demonstrating that a better understanding of AML biology is a pre-requisite for the development of novel therapies to improve treatment outcomes. AML is characterised 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 in adults children and infants.
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 that drive 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 groups who 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 know how, clinical expertise and scientific drive, we have the tools to make major advances in the treatment of AML.
Dysregulated metabolic enzymes mediate vulnerabilities for disease via epigenetic mechanisms
The molecular interactions and crosstalk between epigenetic regulation and cellular metabolism are significantly influenced by diet and metabolism and thus are dependent on nutrient availability. Recently an intersecting mechanism has been described, suggesting that there are under-studied molecular mechanisms that facilitate epigenomic dynamics under perturbed metabolic conditions that may contribute to human disease.
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 the drug response of novel drug or drug combinations, both in vitro and by participating in clinical trials.
- Dissect the metabolic-epigenetic molecular networks in blood cells; highlight their role in mediating cellular responses; and explore their modifiability through dietary and pharmacological interventions for metabolic associated diseases.
Work environment and values
Creating Psychological Safety in the Workplace from HBR IdeaCast.
Dr. Chung-Chau HonTeam Leader, Center for Integrative Medical Sciences, RIKEN, Japan
Looking for a Postdoc or Master position?
We are always interested to recruit motivated students and postdocs!
Please contact Andreas Lennartsson for more information.
Perturbed epigenetic transcriptional regulation in AML with IDH mutations causes increased susceptibility to NK cells.
Palau A, Segerberg F, Lidschreiber M, Lidschreiber K, Naughton AJ, Needhamsen M, Jung LA, Jagodic M, Cramer P, Lehmann S, Carlsten M, Lennartsson A
Leukemia 2023 Jul;():
EpiFactors 2022: expansion and enhancement of a curated database of human epigenetic factors and complexes.
Marakulina D, Vorontsov IE, Kulakovskiy IV, Lennartsson A, Drabløs F, Medvedeva YA
Nucleic Acids Res 2023 Jan;51(D1):D564-D570
RUNX1/CEBPA Mutation in Acute Myeloid Leukemia Promotes Hypermethylation and Indicates for Demethylation Therapy.
Romanova EI, Zubritskiy AV, Lioznova AV, Ogunleye AJ, Golotin VA, Guts AA, Lennartsson A, Demidov ON, Medvedeva YA
Int J Mol Sci 2022 Sep;23(19):
Challenging conventional karyotyping by next-generation karyotyping in 281 intensively treated patients with AML.
Mareschal S, Palau A, Lindberg J, Ruminy P, Nilsson C, Bengtzén S, Engvall M, Eriksson A, Neddermeyer A, Marchand V, Jansson M, Björklund M, Jardin F, Rantalainen M, Lennartsson A, Cavelier L, Grönberg H, Lehmann S
Blood Adv 2021 02;5(4):1003-1016
Functional annotation of human long noncoding RNAs via molecular phenotyping.
Ramilowski JA, Yip CW, Agrawal S, Chang JC, et al
Genome Res 2020 07;30(7):1060-1072
AML displays increased CTCF occupancy associated with aberrant gene expression and transcription factor binding.
Mujahed H, Miliara S, Neddermeyer A, Bengtzén S, Nilsson C, Deneberg S, Cordeddu L, Ekwall K, Lennartsson A, Lehmann S
Blood 2020 07;136(3):339-352
A regulatory role for CHD2 in myelopoiesis.
Shahin Varnoosfaderani F, Palau A, Dong W, Persson J, Durand-Dubief M, Svensson JP, Lennartsson A
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
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, Döhner K, Ekwall K, Lehmann S, Lennartsson A
Blood 2017 02;129(7):e13-e25
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
Transcribed enhancers lead waves of coordinated transcription in transitioning mammalian cells.
Arner E, Daub CO, Vitting-Seerup K, Andersson R, Lilje B, Drabløs F, Lennartsson A, et al
Science 2015 Feb;347(6225):1010-4
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
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, Höglund M, Bullinger L, Döhner K, Lehmann S
Epigenetics 2014 Aug;9(8):1108-19
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, Hoof I, de Hoon M, Itoh M, Nagao-Sato S, Kawaji H, Lassmann T, Carninci P, Hayashizaki Y, Forrest AR, Sandelin A, Ekwall K, Arner E, Lennartsson A,
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, Daub CO, Forrest AR, Lennartsson A, Ekwall K,
Blood 2014 Apr;123(17):e46-57
A promoter-level mammalian expression atlas.
FANTOM Consortium and the RIKEN PMI and CLST (DGT), Forrest AR, Kawaji H, Rehli M, 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, Chen Y, Zhao X, Schmidl C, Suzuki T, Ntini E, Arner E, Valen E, Li K, Schwarzfischer L, Glatz D, Raithel J, Lilje B, Rapin N, Bagger FO, Jørgensen M, Andersen PR, Bertin N, Rackham O, Burroughs AM, Baillie JK, Ishizu Y, Shimizu Y, Furuhata E, Maeda S, Negishi Y, Mungall CJ, Meehan TF, Lassmann T, Itoh M, Kawaji H, Kondo N, Kawai J, Lennartsson A, Daub CO, Heutink P, Hume DA, Jensen TH, Suzuki H, Hayashizaki Y, Müller F, Forrest ARR, Carninci P, Rehli M, Sandelin A
Nature 2014 Mar;507(7493):455-461
Developed Tools and databases
EpiFactors - a tool for cell specific expression of epigenetic regulators: