Epigenomics of leukemia: from mechanisms to therapeutic applications

Abstract

Leukemogenesis is a multistep process in which successive transformational events enhance the ability of a clonal population arising from hematopoietic progenitor cells to proliferate, differentiate and survive. Clinically and pathologically, leukemia is subdivided into four main categories: chronic lymphocytic leukemia, chronic myeloid leukemia, acute lymphocytic leukemia and acute myeloid leukemia. Leukemia has been previously considered only as a genetic disease. However, in recent years, significant advances have been made in the elucidation of the leukemogenesis-associated processes. Thus, we have come to understand that epigenetic alterations including DNA methylation, histone modifications and miRNA are involved in the permanent changes of gene expression controlling the leukemia phenotype. In this article, we will focus on the epigenetic defects associated with leukemia and their implications as biomarkers for diagnostic, prognostic and therapeutic applications.

Modulation of Epigenetic Targets for Anticancer Therapy: Clinicopathological Relevance, Structural Data and Drug Discovery Perspectives

“…In leukemias the role of different epigenetic enzymes has been investigated mainly for acute promyelocytic leukemia (APL) [103,104] and acute myeloid leukemia (AML) [103]. Biological players that have been studied for clinical applications include deacetylases [32,[105][106][107][108], DNA and histone methyltransferases [32,35,103,104,[109][110][111][112][113][114][115][116][117][118][119][120][121][122][123][124][125] and miRNA [104,119,126,127].…”

Histone deacetylase modulators provided by Mother Nature

“…The latter leads to the formation of fusion proteins such as MLL-CBP, MLL-p300, MOZ-CBP, MOZ-p300 or MOZ-TIF2 involved in aberrant gene expression. For example, in a normal state, MOZ controls RUNX1 expression, which is involved in cell differentiation, whereas the fusion protein MOZ-CBP induces the repression of this protein, thus promoting carcinogenesis (Bug and Ottmann 2010;Florean et al 2011). Moreover, chromatin modifications induced by alterations in histone acetylation status of specific genes could be due to aberrant HDAC recruitment triggered by leukemia-associated fusion proteins, such as PLZF-RAR (promyelocytic leukemia zinc finger-retinoic acid receptor-a) or PML-RAR (promyelocytic leukemia-retinoic acid receptor-a) in promyelocytic leukemia.…”

“…The presence of retinoic acid disrupts these inhibitory complexes to the benefit of transcriptional activator complexes, which contain HAT. The fusion-proteins PLZF-RAR and PML-RAR block this dissociation and recruit other enzymes involved in chromatin structure modifications, promoting a drastic inhibition of transcription (Florean et al 2011;Minucci and Pelicci 2006). This mechanism is responsible for aberrant recruitment of HDACs to specific promoters involved in differentiation and impairs p53 functions, which play an important role in leukemogenesis.…”

“…In addition to histone acetylation, other histone modifications such as methylation are involved in chromatin structure and act together with DNA methylation on TSG silencing ( Fig. 2; Florean et al 2011;Hassan et al 2007;Jones et al 1998;Wade et al 1999). Altogether, these mechanisms are implicated in apoptosis resistance, differentiation arrest, cell cycle perturbations leading to aberrant proliferation associated with tumorigenesis and tumor aggressiveness, including invasiveness and metastasis.…”

Biology of CML stem cells: the basis for clinical heterogeneity?

“…18 The HOX4A gene is frequently hypermethylated in CML and in lymphoid malignancies and may be associated with poor prognosis. 19 Conversely, it appears that downregulation of BIM expression is associated with reduced optimal responses to imatinib, 20 a finding that links to some extent with the negative effect of BIM deletions.…”