Epialleles and epiallelic heterogeneity in hematological malignancies.

DNA methylation has a well-established role in the pathogenesis, prognosis, and response to treatment in all the spectra of hematological malignancies. However, most of the data reported involve average DNA methylation observed in a sample. The emergence of bisulfite sequencing methods such as enhanced reduced representation that permit analyze adjacent CpGs led to exciting findings. Among these are the epialleles shift and the resulting epigenetic heterogeneity observed in leukemias and lymphomas. Epialleles seem to have an influential role as the cause of mutations that characterize leukemias, may stratify groups with different prognosis and response to treatment, and may be redistributed in the genome at different time points of the disease promoting activation of alternate transcriptional networks. Epiallelic shift may be responsible for the intratumor heterogeneity observed within the cells of the same tumor which increases with disease aggressiveness. It may also responsible for the interpatient heterogeneity explaining why blood cancers exhibit different behavior among different patients. Understanding better epiallelic conformation and the consequent chromatin conformational changes and the pathways that may be affected will permit deeper understanding of hematological malignancies pathogenesis and treatment.

Long non-coding RNAs and MYC association in hematological malignancies.

Long non-coding RNAs (lncRNAs) have an established role in cell biology. Among their functions is the regulation of hematopoiesis. They characterize the different stages of hematopoiesis in a more lineage-restricted expression pattern than coding mRNAs. They affect hematopoietic stem cell renewal, proliferation, and differentiation of committed progenitors by interacting with master regulators transcription factors. Among these transcription factors, MYC has a prominent role. Similar to MYC's transcriptional activation/amplification of protein coding genes, MYC also regulates lncRNAs' expression profile, while it is also regulated by lncRNAs. Both myeloid and lymphoid malignancies are prone to the association of MYC with lncRNAs. Such interaction inhibits apoptosis, enhances cell proliferation, deregulates metabolism, and promotes genomic instability and resistance to treatment. In this review, we discuss the recent findings that encompass the crosstalk between lncRNAs and describe the pathways that very probably have a pathogenetic role in both acute and chronic hematologic malignancies.

Enhancers and MYC interplay in hematopoiesis.

Transcription requires the fine interplay between enhancers and transcription factors. Enhancers are able to activate transcription of genes involved in normal cell biology, whereas aberrant enhancer activity leads to oncogenesis. MYC is a well-established proto-oncogene involved in half of human cancers amplifying the output of its targets. The crosstalk between MYC and enhancers is known for many years since the discovery of IgH enhancer juxtaposition with MYC in high-grade lymphomas. Here, we focus mainly in the enhancers surrounding MYC in the 8q24 locus. That region comprises several enhancers that associate with other transcription factors, transmembrane receptors, and fusion genes composing complex regulatory networks aberrantly expressed in almost all types of hematological malignancies. Understanding the nature of these interactions in normal blood cells and in leukemias/lymphomas will expand MYC targeting options in the armamentarium against hematological cancers.