Immune-epigenetic crosstalk in haematological malignancies

Abstract

Haematological malignancies comprise a diverse set of lymphoid and myeloid neoplasms which can arise during any stage of haematopoiesis in the bone marrow. Accumulating evidence suggests that chronic inflammation generated by inflammatory cytokines secreted by tumour and the tumour-associated cells within the bone marrow microenvironment initiates signalling pathways in malignant cells, resulting in activation of master transcription factors including Smads, STAT3, and NF-κB which confer cancer stem cell phenotypes and drive disease progression. Deciphering the molecular mechanisms for how immune cells interact with malignant cells to induce such epigenetic modifications, specifically DNA methylation, histone modification, expression of miRNAs and lnRNAs to perturbate haematopoiesis could provide new avenues for developing novel targeted therapies for haematological malignancies. Here, the complex positive and negative feedback loops involved in inflammatory cytokine-induced cancer stem cell generation and drug resistance are reviewed to highlight the clinical importance of immune-epigenetic crosstalk in haematological malignancies.

Keywords: cancer; epigenetics; leukemia; niche; stem cell.

FIGURE 1

Graphic representation of the cells and soluble molecules present in the bone marrow microenvironment. The perivascular niche favours the uptake of oxygen and nutrients, whilst cells and soluble factors regulate HSC homing, mobilisation, quiescence, self-renewal and lineage commitment. Created with BioRender.com.

FIGURE 2

Graphic representation of epigenetic alterations induced by cancer–immune cell communication in haematological malignancies. Components of the BM microenvironment release cytokines which activate downstream signalling pathways such as NF-κB, SMAD and JAK/STAT, which in turn activates the transcription of chromatin modifiers. They induce epigenetic changes in cancer cells and transform their phenotype, increasing their self-renewal, survival and thereby promoting disease progression. Created with BioRender.com.