Translational research
DFG-funded projects:
Influence of Plcg1 on hematopoetic and leukemic stem cells: In this project we investigate the effects of Plcg1 signaling on the maintenance of hematopoietic and leukemic stem cells in vitro and in vivo. Analysis of Plcg1 dependent downstream signaling and global assessment of transcriptional and proteomic changes depending on Plcg1 activity will be conducted in murine and human cells. We aim to characterize this signaling molecule as a potential therapeutic target in AML.
PI’s: Prof. Dr. F. Heidel & Dr. T. Schnöder
Funding Agency: Deutsche Forschungsgemeinschaft (DFG)
Funding ID: HE6223/6-1 und SCHN1556/1-1
Funding Period: 2017-2020
Unlocking the curative potential of ATRA in non-APL AML: Identification of the mechanisms underlying successful induction of differentiation with ATRA and LSD1 inhibitors.
Treatment failure, relapse and mortality of acute myeloid leukemias (AML) are unacceptably high and it is reasonable to predict that cure rates will not improve unless treatment modalities alternative to conventional chemotherapy and bone marrow transplantation are developed.
A hallmark of AML is a failure to properly differentiate and the retinoic acid receptor (RAR) ligand all-trans-retinoic acid (ATRA) has demonstrated remarkable efficacy in inducing differentiation in a sub-type of AML, acute promyelocytic leukemia (APL). However, ATRA-based treatment has failed to replicate this success in non-APL AML. We recently demonstrated a critical role for the histone H3 lysine 4 mono/di demethylase LSD1 as a negative regulator of the ATRA-mediated myeloid differentiation pathway. Treatment with inhibitors of LSD1 (LSD1i) dramatically potentiated the pro-differentiative effects of ATRA and diminished the clonogenic capacity of AML cells in vitro and in vivo. The objective of this project proposal is to thoroughly unravel the mechanisms underlying the pro-differentiative effects of LSD1i and ATRA and to establish the basis for supplementary strategies to further unlock its curative potential in non-APL AML.
Project leader: Dr. Tino Schenk
Funding agency: German Research Council
Funding ID: : DFG SCHE 1909/2-1
Funding Period:: 2015-2018
Evolutionary conserved regulators of stem cell properties as well as RNA-/DNA-binding proteins have been shown to influence hematopoietic stem cell-polarity and –division. Recently, we were able to characterize a polarity regulator and member of the ‘Scribble’ polarity complex (lethal giant larvae homolog 1 – Llgl1) and provided evidence for its role in regulation of HSC biology. Loss of Llgl1 resulted in competitive advantage of hematopoietic stem cells (HSC) and Llgl1 KO HSC revealed a higher degree of stress-resistance. Despite an increase in cell cycle, Llgl1 KO HSC did not exhaust. Moreover, low expression of Llgl1 in primary patient blasts was associated with dismal prognosis and decreased overall survival of patients with acute myeloid leukemia. In the proposed study we aim to investigate the impact of ‘Scribble’ polarity complex on hematopoietic stem cells. We will characterize the functional relevance using a conditional knockout mouse model for the central complex member ‘Scribble’.
PI: Prof. Dr. F. Heidel
Funding Agency: Deutsche Forschungsgemeinschaft (DFG)
Funding ID: HE6223/2-1
Funding Period: 2014-2018
Foundation-funded projects:
Blockade of ROS as a novel therapeutic strategy in AML: FLT3-ITD mutated AML has a dismal prognosis and novel therapeutic options are clearly warranted. In our previous work we were able to provide first evidence for the role of ROS in transformation of FLT3-ITD positive cells (Jayavelu et al. Leukemia 2016). ROS production is driven through STAT-signaling by NOX4, which is a direct transcriptional target of STAT5. We aim to investigate inhibition of ROS production as a potential therapeutic strategy for FLT3-ITD mutated AML.
PI’s: Prof. Dr. F. Heidel & Prof. Dr. F. D. Böhmer
Funding Agency: Deutsche Krebshilfe e.V.
Funding ID: 70112607
Funding Period: 01.08.2017 – 31.07.2020
The role of bone marrow stromal cells in the malignant transformation of multiple myeloma plasma cells. With this project we aim at identifying factors within the bone marrow microenvironment (i.e. cells and factors others than blood precursor cells within the bone marrow) that lead to the malignant transformation of plasma cells and to plasma cells related disorders.
PI’s: Dr. A. M. Brioli, Prof. Dr. A. Hochhaus, Prof. Dr. M. v. Llilienfeld-Toal
Funding agencies: Else-Kröner Fresenius Stiftung, Else-Kröner-Forschungskolleg Jena ‚AntiAge’
Funding Period:: 2017-2020