Dissecting molecular basis and cellular heterogeneity of slow progressing 'smoldering' AMLs of the elderly

点击翻译按钮获取中文摘要

Acute Myeloid leukemia is an aggressive and highly complex disease caused by a combination of genetic lesions likely originating in normal hematopoietic stem cells. Typically patients present with a nearly exponential increase of leukocytes and blasts in the peripheral blood resulting in a lethal leukostasis within days. In elderly patients, or in patients with secondary AMLs, the course of the AML disease is often less aggressive, and sometimes untreated patients show stable blast and leukocyte counts over several months. Interestingly, some of those AML patients have higher blast counts in the PB than in the BM. These rare smoldering or slow progressing AMLs are of special interest, as they might represent an earlier disease stage of AML with aberrant mobilization of blasts into the peripheral blood due to failure of the bone marrow niche or altered regulation of homing receptors like CXCR4Since these types of AML in the elderly are rare and understudied, the mechanistic basis for these AMLs remains poorly understood and enigmatic. Within this Forschergruppe, we (A08) will first characterize more than 20 smoldering/slow progressing AML by detailed flow cytometric analysis with the inclusion of leukemic stem cell (LSC) markers as well as CXCR4, which may serve as a biomarker for these AMLs. We will determine the mutational landscape to these diseases by exome sequencing and will functionally identify LSC containing populations by transplantation into immune-compromised recipient mice. These LSCpos and LSCneg sub-populations will then be molecularly characterized at the genome wide level using a multi-omics approach. This includes determination of the methylome, transcriptome and mapping of chromatin accessibility. Correlation of these genome wide data sets using bioinformatics and computational approaches will reveal the overall molecular landscapes of LSCs and blasts in these AMLs with the goal to identify novel biomarkers for stratification and novel targets to therapeutically target this disease. Finally, we will specifically analyse MYC and a novel super-enhancer driving this key transcription factor in normal hematopoietic and AML stem cells. Together with the other EPIGRAM partners we will not only determine changes in the epigenetic landscape during leukemogenesis and LSC formation and function, but will focus specifically onto the MYC enhancer network as well as up- and downstream events, which are likely influencing aggressiveness, and therapy response. Altogether, we aim to explore the so far little explored smoldering AMLs of the elderly at a detailed genomic level, but are also studying the cause of differential blast mobilization and the role of CXCR4 as well as epigenetic control of MYC via its super-enhancer in AMLs. This project will not only reveal novel insights into the molecular make up of such indolent AMLs, but also may provide novel stratification and therapy tools to better characterize and target this subtype of AML.