Targeting mechanisms for epigenetic gene silencing guarding proliferation and survival in multiple myeloma and infant acute lymphoblastic leukemia - Implications for biology and therapy

The main objective is to dissect a disease-specific global epigenetic pattern of clinical importance in multiple myeloma (MM) and infant acute lymphoblastic leukemia (iALL), to increase our understanding of how epigenetic abnormalities contribute to drug resistance, to define sub-groups of patients that may benefit from drugs in clinical use, to evaluate intra-tumoral subpopulations on an epigenetic and metabolic level contributing to pathogenesis, and to explore if the altered epigenome constitutes a target for personalized medicine.

Our approach is based on that genome-wide studies on the complex interplay between different epigenetic, metabolic mechanisms and the transcriptome with single-cell resolution in MM and iALL are largely lacking.

This proposal is enabled by a translational Nordic network with pre-clinical and clinical expertise, established bioinformatics collaborations and functional analysis in patient cohorts and tumor models.

We now aim to 1) use applied machine-based learning on single cell transcriptomics, and 2) integrative multimodal analysis of the epigenomic states at single-cell resolution in large cohorts.

In addition, we will 3) functionally evaluate the interplay between the metabolic circuitry and epigenetic non-mutational reprogramming contributing to tumorigenicity, 4) define the tumor specific transcriptome and intraclonal alterations, and 5) investigate the therapeutic potential of therapies to metabolic and epigenetic targets.