The major focus of the laboratory´s translational research programme is to characterize and target cancer stem cells (CSCs), as well a to improve prognostification in patients with Acute Myeloid Leukemia (AML).
The laboratory´s main focus is to conduct comprehensive genomics and functional analyses on bone marrow populations equating to normal hematopoietic stem and progenitor cells that are sorted from healthy subjects and AML patients. Purified AML populations are sequenced with the aim to map the clonal hierarchies and therapy-resistant subclones in AML patients. In addition, gene expression profiles of purified AML populations are compared with those of their normal counterparts in order to identify AML signatures of differentially expressed genes in cancer versus normal cells. The identified AML signatures are subsequently combined with clinical and conventional diagnostic data to establish novel genomics strategies for improved prognostification of AML. Finally, the AML signatures are used to unravel “oncogenic” signaling pathway activities in AML patients and test inhibitory drugs for these pathways in preclinical therapeutic programmes (Fig.1), with the ultimate goal to identify novel drugs for the treatment of AML patients.
Figure 1. Flowchart of genomics screen for the identification and targeting of “oncogenic” pathways, RTKs and other kinases in AML patients.
BM samples are collected from healthy subjects and AML patients, and normal as well as leukemic BM populations with the immunophenotypes of normal stem and progenitor cells are purified by flow cytometry based cell sorting. Purified BM populations are subjected to microarray analysis and the resultant gene expression profiles are analyzed by a set of bioinformatics methodologies including GSEA (gene set enrichment analysis). The bioinformatics strategy is designed to define aberrant high expression of RTKs/other kinases and aberrant pathway activity in AML populations (i.e. LSCs and leukemic bulk cells) compared to their normal counterparts. Subsequently, specific inhibitory drugs selected and validated with respect to their ability to inhibit growth and survival of AML cells in vitro and in xenograft models. For details see Rapin et al. Blood, 2014, Theilgaard-Mönch et al. Leukemia 2011, and Marstrand et al. Leukemia, 2010.
Rapin N, Bagger FO, Jendholm J, Mora-Jensen H, Krogh A, Kohlmann A, Thiede C, Borregaard N, Bullinger L, Winther O, Theilgaard-Mönch K and Porse BT (shared last authorship). Comparing cancer vs. normal gene expression profiles identifies new disease entities and common transcriptional programs in AML patients. Blood. 2014 Feb 6;123(6):894-904.
Larsen MT, Hother C, Häger M, Pedersen CC, Theilgaard-Mönch K, Borregaard N, Cowland JB. MicroRNA Profiling in Human Neutrophils during Bone Marrow Granulopoiesis and In Vivo Exudation.
PLoS One. 2013;8(3):e58454.
Bagger FO, Rapin N, Theilgaard-Mönch K, Kaczkowski B, Thoren LA, Jendholm J, Winther O, Porse BT. HemaExplorer: a database of mRNA expression profiles in normal and malignant haematopoiesis.
Nucleic Acids Res. 2013 Jan;41(Database issue):D1034-9.
Hasemann MS, Schuster MB, Frank AK, Theilgaard-Mönch K, Pedersen TÅ, Nerlov C, Porse BT. Phosphorylation of Serine 248 of C/EBPα Is Dispensable for Myelopoiesis but Its Disruption Leads to a Low Penetrant Myeloid Disorder with Long Latency.
PLoS One. 2012;7(6):e38841. Epub 2012 Jun 8.
Bagger FO, Rapin N, Theilgaard-Mönch K, Kaczkowski B, Jendholm J, Winther O, Porse B. HemaExplorer: a Web server for easy and fast visualization of gene expression in normal and malignant hematopoiesis.
Blood. 2012 Jun 28;119(26):6394-5.