Epigenetics of hematopoiesis and hematological malignancies

Abstract

Hematological malignancies comprise a diverse set of lymphoid and myeloid neoplasms in which normal hematopoiesis has gone awry and together account for ∼10% of all new cancer cases diagnosed in the United States in 2016. Recent intensive genomic sequencing of hematopoietic malignancies has identified recurrent mutations in genes that encode regulators of chromatin structure and function, highlighting the central role that aberrant epigenetic regulation plays in the pathogenesis of these neoplasms. Deciphering the molecular mechanisms for how alterations in epigenetic modifiers, specifically histone and DNA methylases and demethylases, drive hematopoietic cancer could provide new avenues for developing novel targeted epigenetic therapies for treating hematological malignancies. Just as past studies of blood cancers led to pioneering discoveries relevant to other cancers, determining the contribution of epigenetic modifiers in hematologic cancers could also have a broader impact on our understanding of the pathogenesis of solid tumors in which these factors are mutated.

Resetting the epigenetic balance of Polycomb and COMPASS function at enhancers for cancer therapy

“…Genome-wide sequencing of cancer has identified frequent mutations within COMPASS subunits, suggesting that misregulation of their activities plays an important role in pathogenesis 1,15 . For instance, chromosomal translocations generate MLL fusion proteins that constitutively activate the posterior HOXA cluster, resulting in aberrant self-renewal of hematopoietic progenitors and leukemia development 16,17 . In diffuse large B cell lymphoma and follicular lymphoma, MLL4 (KMT2D) acts as a tumor suppressor, and mutations within its catalytic domain promote lymphomagenesis 18,19 .…”

Wolf-Hirschhorn Syndrome Candidate 1 Is Necessary for Correct Hematopoietic and B Cell Development

“…Methylation at H3K36 has been associated with regulation of transcription, splicing, DNA replication and DNA repair (Wagner and Carpenter, 2012). So far, a specific role for WHSC1 in the immune defects associated to WHS patients has not been proven and, in general, the functions of the members of the NSD family in normal hematopoiesis have not been investigated, even though they are recurrently involved in hematopoietic malignancies (Shilatifard and Hu, 2016). Here, we present in vivo genetic evidence showing that Whsc1 deficiency impairs normal hematopoietic development at several stages and lineages, and particularly affects B cell differentiation and mature B cell function.…”

LncRNA Spehd regulates hematopoietic stem cells and progenitors and is required for multilineage differentiation

“…DNA methylation changes are associated with regulatory areas where lineagespecific transcription factors bind (Bock et al, 2012;Hodges et al, 2011), and, consequently, the different DNA methyl transferases have been shown to play essential roles in hematopoietic differentiation (Challen et al, 2011;Trowbridge et al, 2009). Hematopoiesis is also highly sensitive to alterations to chromatin modifiers, both during normal differentiation (Kerenyi et al, 2013) and during malignant transformation (reviewed in (D. Hu and Shilatifard, 2016)).…”