Leukaemogenesis: more than mutant genes

Abstract

Acute leukaemias are characterized by recurring chromosomal aberrations and gene mutations that are crucial to disease pathogenesis. It is now evident that epigenetic modifications, including DNA methylation and histone modifications, substantially contribute to the phenotype of leukaemia cells. An additional layer of epigenetic complexity is the pathogenetic role of microRNAs in leukaemias, and their key role in the transcriptional regulation of tumour suppressor genes and oncogenes. The genetic heterogeneity of acute leukaemias poses therapeutic challenges, but pharmacological agents that target components of the epigenetic machinery are promising as a component of the therapeutic arsenal for this group of diseases.

Figure 1. Leukemia fusion proteins and epigenetic deregulation

Oncogeneic fusion proteins such as AML1-ETO, CBFB-MYH11, and PML-RARA recruit transcriptional co-repressor complexes (including NCOR1 and SMRT) which result in the loss of histone acetylation and the acquisition of repressive histone modification marks such as histone H3 lysine 9 (H3K9) methylation and H3K27 trimethylation, as well as DNA methylation, and thereby a closed chromatin structure. This leads to transcriptional silencing of various target genes including genes that are critical for hematopoietic differentiation. Epigenetic or transcriptional therapy (targeting the fusion proteins, components of the corepressor complexes or downstream effectors such as miRNAs) has the potential to reverse these changes leading to histone acetylation, and acquisition of active marks such as H3K4 methylation, an open chromatin structure with subsequent transcriptional activation and differentiation of the leukemic clone. HDACs, histone deacetylases; DNMT, DNA methyltransferases; HMT, histone methyltransferases; NCOR1, nuclear receptor co-repressor 1; SMRT, the silencing mediator of retinoic acid and thyroid hormone receptor, also known as NCOR2; TF, transcription factor; Ac, histone acetylation; RNApolII, RNA polymerase II.

Figure 2. Involvement of miRNAs in acute leukemia

miRNAs that are up-regulated (in purple) or down-regulated (in blue) in a subtype of acute leukemia are shown. Some miRNAs are associated with specific leukemia subtypes and thereby may be able to serve as biomarkers for classification and diagnosis of these subtypes. For example, miR-126 in CBF leukemia (leukemias with t(8;21) or inv(16)), , mir-17-92 in MLL-associated leukemia (those with t(11q23)), , miR-196b in MLL-associated leukemia, , and in AML with NPM1 mutations, miR-224, miR-382 and miR-376 family in APL (t(15;17)), , , miR-10a and b in AML with NPM1 mutations, , and miR-155 in AML with FLT3-ITD, are likely to be such markers. AML, acute myeloid leukemia; ALL, acute lymphoblastic leukemia; FAB, French-American-British (FAB) classification; FAB, French American British Classification, MO, Acute myeloid leukemia with minimal differentiation; M1 Acute myeloid leukemia without differentiation; M2, Acute myeloid leukemia with maturation, M3, Acute promyelocytic leukemia; M4, Acute myelomonocytic leukemia, M5, Acute monoblastic leukemia; M6, Acute erythroleukemia; M7, acute megakaryoblastic leukemia; HSC, hematopoietic stem cell; MPP, multipotent progenitor cell; CMP, common myeloid progenitor; CLP, common lymphoid progenitor; MEP, megakaryocyte-erythrocyte progenitor; GMP, granulocyte-macrophage progenitor; EP, erythroid progenitor; Meg-P, megakaryocyte progenitor; GP, granulocyte progenitor; MP, monocyte progenitor.