Project Details
Projekt
Dissecting AML transcriptome and chromatin networks by single cell sequencing to reveal cell heterogeneity and drug response mechanisms
Applicants
Dr. Jan-Philipp Mallm; Professor Dr. Karsten Rippe
Subject Area
Hematology, Oncology
Term
from 2017 to 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 336840530
Acute myeloid leukemia (AML) exhibits a large cellular heterogeneity on both the genetic and the epigenetic level. At the time of diagnosis most cases of AML are characterized by the presence of a tumor initiating clone and additional sub-clones that later evolve into therapy resistant cells. Single cell sequencing (sc-seq) methods are ideally suited to detect the presence of a relatively small hematopoietic subpopulation of leukemic stem cells that maintain and reinitiate leukemia, and to identify subpopulations that are resistant to a given drug. In the next funding period, we will complement our successful high-throughput analysis on the Chromium platform with plate-based methods for the single cell work in projects A01-A08. The plate-based technologies allow it to analyze samples with low input cell numbers with much higher flexibility and a variety of readouts. Since changes in DNA methylation are at the core of the epigenetic features analyzed in many FOR2674 projects we will also establish an efficient single cell DNA methylome analysis. Furthermore, we will provide multi-omics sc-seq approaches, such as CITE-seq or single-cell whole genome bisulfite sequencing coupled to mapping accessible chromatin. Finally, Z01 (in collaboration with A02), will continue the work on the identification of epigenetic molecular deregulation and resistance mechanisms for IDH mutated AML as a prototypic application for the novel sc-seq methods. Here, also targeted scDNA-seq will be included to reveal the clonal substructure of the tumor and its evolution during treatment with drugs that inhibit mutated IDH. The advanced combination of different types of sc-seq methods and applications provided by Z01 will dissect AML heterogeneity and reveal novel molecular features of its pathophenotype.
DFG Programme
Research Units
