Epigenetics and mutations in chronic myeloproliferative neoplasms

Abstract

T he BCR-ABL1-negative classic myeloproliferative neoplasms, polycythemia vera (PV), essential thrombocytemia (ET) and primary myelofibrosis are clonal stem cell disorders associated with an increased production of mature blood cells belonging preferentially to one cell linage.1 They share substantial phenotypic mimicry, can undergo phenotypic shifts (from PV to ET and vice versa) as well as evolution to myelofibrosis (post-PV/post-ET myelofibrosis), and all eventually progress to leukemia. The hypothesis that hypersensitivity of hematopoietic stem and progenitor cells to cytokines might largely account for the pathogenesis of myeloproliferative neoplasms has been corroborated by the discovery of mutations that affect cytoplasmic proteins involved in cytokine signaling, either resulting in a gain-of-function (JAK2 and MPL) or a loss-of-function (CBL and LNK). Dysregulation of tyrosine kinases is a recurrent theme in chronic myeloid neoplasms, as exemplified by the constitutive activation of ABL caused by oligomerization of the BCR-ABL fusion protein in chronic myelogenous leukemia, the gain-of-function mutation of the tyrosine kinase receptor c-KIT in mastocytosis, and the activation of platelet-derived growth factor receptor-α or -b and fibroblast growth factor receptor in hypereosinophilic disorders. However, high-throughput genomic analyses of myeloproliferative neoplasms have recently identified a second group of mutations that affect proteins involved in the epigenetic regulation of transcription, such as TET2, ASXL1 and EZH2.2 These abnormalities can occur in association and/or with mutations targeting tyrosine kinases. (5mC) to 5-hydroxymethylcytosines (5hmC). EZH2 is the catalytic subunit of the PRC2 complex and trimethylates Lys-27 of histone H3 (H3K27) leading to transcriptional repression of target genes. ASXL1 exists in chromatin-associated multiprotein complexes, together with PcG and TrxG proteins, involved in modifications of chromatin configuration that result in repressed and enhanced transcription, respectively, in a cellular context-specific manner. Described loss-of-function mutations of EZH2, TET2 and ASXL1 presumably lead to suppression of catalytic activity of these enzymes. Mutant JAK2, but not the wild-type protein, phosphorylates protein arginine methyltransferase 5 (PRMT5), causing inhibition of its arginine methyltransferase activity on H2A and H4 (H2AR3me and H4R3me). JAK2 also phosphorylates Tyr 41 (Y41) on histone H3 leading to decreased HP1α binding to chromatin; the displacement of HP1α is magnified after enhanced H3Y41 phosphorylation due to JAK2V617F.

Phase II trial of panobinostat, an oral pan‐deacetylase inhibitor in patients with primary myelofibrosis, post–essential thrombocythaemia, and post–polycythaemia vera myelofibrosis

“…Recently, mutations in genes involved in regulating the epigenome in myeloid malignancies (e.g. DNMT3A , TET2 , IDH1 , IDH2 , ASXL1 , and EZH2 ) have been described in MPN (Tefferi & Vainchenker, ; Vannucchi & Biamonte, ). This raises the possibility that an agent, such as panobinostat, which not only targets the JAK/STAT pathway but can potentially also target the deregulated epigenome in myeloid stem and progenitor cells, may represent a novel approach for the treatment of patients with MPN (Fiskus et al , ,b).…”

Epigenetics in Myeloproliferative Neoplasms

“…EZH2 (enhancer of zeste homolog 2) is another key regulator of PRC2 . EZH2 is present on chromosome 7 and is overexpressed in solid tumours such as lymphoma.…”

A data-driven network model of primary myelofibrosis: transcriptional and post-transcriptional alterations in CD34+ cells

“…Specifically, the discoveries of somatic mutations in JAK2, MPL and CALR genes have improved patients' stratification and molecular characterization highlighting the role of Jak-STAT signaling in MPN pathogenesis. However, several evidences indicate that these mutations are not sufficient for disease initiation and progression and that the phenotypes of the disease are highly heterogeneous, suggesting that other unknown genetic or epigenetic factors might be involved 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 and also that the mutation order could matter: 16 driver mutations can precede or follow additional somatic mutations in other myeloid genes. Interestingly, recently, it has been demonstrated that most of these genes are associated with age-related clonal hematopoiesis in normal elderly subjects, suggesting that pre-malignant clones may be present many years before disease develops and are required, but insufficient, to result in disease.…”