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Haematological malignancies remain clinically challenging due to the incomplete understanding of the molecular mechanisms that drive disease progression and therapeutic resistance. Multiple myeloma (MM) is a heterogeneous malignancy characterised by the clonal expansion of malignant plasma cells within the bone marrow. Although recurrent genetic alterations contribute to disease development, genetic lesions alone are insufficient to establish malignancy. Instead, epigenetic reprogramming plays a central role in shaping the transcriptional landscape that sustains tumour growth and survival. 

In paper I we explored the impact of combined G9a and DNMTs inhibition in MM. Dual targeting exerted synergistic anti-tumour effects, reprogramming gene expression toward tumour suppression and increased apoptosis. Moreover, in vivo combination treatment significantly reduced tumour burden compared with single agents. Together, these results uncovered a cooperative epigenetic axis driving MM progression and highlight novel therapeutic vulnerability. In paper II we investigated whether overexpressed lncRNAs cooperate with PRC2 to mediate gene silencing in MM. By integrating RIP-seq and RNA-seq analyses, we identified PVT1 as a key lncRNA interacting with EZH2. Genome-wide analyses revealed that PVT1 guides PRC2 silenced tumour suppressor and pro-apoptotic genes. Disruption of either EZH2 or PVT1 restored transcription of tumour suppressor genes, defining a PVT1-PRC2 regulatory axis that contributes to MM pathogenesis.  In paper III we further explored lncRNA-mediated PRC2 recruitment by characterizing the role of PCAT1 in MM. We demonstrated a direct interaction between PCAT1 and PRC2 and showed that PCAT1 overexpression correlates with poor overall survival and advanced disease stage. Integrative transcriptomic analyses revealed that the PCAT1-PRC2 axis regulates gene programs linked to MM pathogenesis and identified SLC44A2 and PIK3CD as novel candidate tumour suppressor targets, supporting a broader role for lncRNAs-driven epigenetic remodelling. 

Infant acute lymphoblastic leukaemia (iALL) is an aggressive haematological malignancy that arises in children below one year of age and is characterised by extremely poor clinical outcome. In Paper IV, we used scRNA-seq to characterise disease heterogeneity in iALL. We found that KMT2A status defined distinct transcriptional states within shared cellular compartments. KMT2A-rearranged iALL was enriched for immature, highly proliferative, and immune-evasive programs. In contrast, KMT2A-germline cases showed more differentiated lymphoid states and increased immune activation. These differences reflect transcriptional reprogramming rather than distinct cell types. Together, this highlights subtype-specific biology with potential therapeutic implications.