Dynamics of epigenetic modifications in leukemia

Abstract

Chromatin modifications at both histones and DNA are critical for regulating gene expression. Mis-regulation of such epigenetic marks can lead to pathological states; indeed, cancer affecting the hematopoietic system is frequently linked to epigenetic abnormalities. Here, we discuss the different types of modifications and their general impact on transcription, as well as the polycomb group of proteins, which effect transcriptional repression and are often mis-regulated. Further, we discuss how chromosomal translocations leading to fusion proteins can aberrantly regulate gene transcription through chromatin modifications within the hematopoietic system. PML-RARa, AML1-ETO and MLL-fusions are examples of fusion proteins that mis-regulate epigenetic modifications (either directly or indirectly), which can lead to acute myeloblastic leukemia (AML). An in-depth understanding of the mechanisms behind the mis-regulation of epigenetic modifications that lead to the development and progression of AMLs could be critical for designing effective treatments.

Figure 1:

Structure of the most frequent fusion proteins in AML. PML–RARα, AML1–ETO, CBFβ-MYH11 and the different chromosomal translocations involving the N-terminus domain of MLL are the main AML-associated oncofusion proteins. Ring, really interesting gene; B1 and B2, B-boxes 1 and 2; CC, coiled-coil; DBD, DNA-binding domain; LBD, ligand-binding domain; RHD, Runt homology domain; NHR, nervy homology regions; HABD, high-affinity binding domain; ATH, AT-hook motifs; SNL, speckled nuclear localization sites; RD, repression domain. Note that the MLL fusion is not depicted in scale.

Figure 2:

Main epigenetic mechanisms of transcription deregulation by AML fusion proteins. The aberrant recruitment of epigenetic machineries to the promoters of key genes in differentiation by fusion proteins is a central step to disrupt normal gene transcription regulation and thus trigger AML. The mechanisms to deregulate transcription are specific for each oncofusion protein, being determined by the characteristics of its moieties.

Figure 3:

AML development as a multistage process. Chromosomal translocations in either HSCs or committed progenitors induce a pre-leukemic state in which further mutations will lead to AML development. Within the AML cell population carrying the mutations implicated in the pathogenesis, the LSCs subpopulation will maintain and propagate the AML phenotype.