Cytokine-Regulated Phosphorylation and Activation of TET2 by JAK2 in Hematopoiesis.

Even though the Ten-eleven translocation (TET) enzymes catalyze the generation of 5-hydroxymethylcytosines required for lineage commitment and subsequent differentiation of stem cells into erythroid cells, the mechanisms that link extracellular signals to TET activation and DNA hydroxymethylation are unknown. We demonstrate that hematopoietic cytokines phosphorylate TET2, leading to its activation in erythroid progenitors. Specifically, cytokine receptor-associated JAK2 phosphorylates TET2 at tyrosines 1939 and 1964.

High resolution integrative analysis reveals widespread genetic and epigenetic changes after chronic in-vitro acid and bile exposure in Barrett's epithelium cells.

Barrett's epithelium (BE) is a premalignant condition resulting from chronic gastroesophageal reflux that may progress to esophageal adenocarcinoma (EAC). Early intervention holds promise in preventing BE progression. However, identification of high-risk BE patients remains challenging due to inadequate biomarkers for early diagnosis.

Genome-wide hydroxymethylation tested using the HELP-GT assay shows redistribution in cancer.

5-hydroxymethylcytosine (5-hmC) is a recently discovered epigenetic modification that is altered in cancers. Genome-wide assays for 5-hmC determination are needed as many of the techniques for 5-methylcytosine (5-mC) determination, including methyl-sensitive restriction digestion and bisulfite sequencing cannot distinguish between 5-mC and 5-hmC. Glycosylation of 5-hmC residues by beta-glucosyl transferase (β-GT) can make CCGG residues insensitive to digestion by MspI.

Myeloma is characterized by stage-specific alterations in DNA methylation that occur early during myelomagenesis.

Epigenetic changes play important roles in carcinogenesis and influence initial steps in neoplastic transformation by altering genome stability and regulating gene expression. To characterize epigenomic changes during the transformation of normal plasma cells to myeloma, we modified the HpaII tiny fragment enrichment by ligation-mediated PCR assay to work with small numbers of purified primary marrow plasma cells. The nano-HpaII tiny fragment enrichment by ligation-mediated PCR assay was used to analyze the methylome of CD138(+) cells from 56 subjects representing premalignant (monoclonal gammopathy of uncertain significance), early, and advanced stages of myeloma, as well as healthy controls.

High resolution methylome analysis reveals widespread functional hypomethylation during adult human erythropoiesis.

Differentiation of hematopoietic stem cells to red cells requires coordinated expression of numerous erythroid genes and is characterized by nuclear condensation and extrusion during terminal development. To understand the regulatory mechanisms governing these widespread phenotypic changes, we conducted a high resolution methylomic and transcriptomic analysis of six major stages of human erythroid differentiation. We observed widespread epigenetic differences between early and late stages of erythropoiesis with progressive loss of methylation being the dominant change during differentiation.

Methylome profiling reveals distinct alterations in phenotypic and mutational subgroups of myeloproliferative neoplasms.

Even though mutations in epigenetic regulators frequently occur in myeloproliferative neoplasms, their effects on the epigenome have not been well studied. Furthermore, even though primary myelofibrosis (PMF) has a markedly worse prognosis than essential thrombocytosis or polycythemia vera, the molecular distinctions between these subgroups are not well elucidated. We conducted the HELP (HpaII tiny fragment enriched by LM-PCR) assay to study genome-wide methylation in polycythemia vera, essential thrombocytosis, and PMF samples compared with healthy controls.

Aberrant epigenetic and genetic marks are seen in myelodysplastic leukocytes and reveal Dock4 as a candidate pathogenic gene on chromosome 7q.

Myelodysplastic syndromes (MDS) are characterized by abnormal and dysplastic maturation of all blood lineages. Even though epigenetic alterations have been seen in MDS marrow progenitors, very little is known about the molecular alterations in dysplastic peripheral blood cells. We analyzed the methylome of MDS leukocytes by the HELP assay and determined that it was globally distinct from age-matched controls and was characterized by numerous novel, aberrant hypermethylated marks that were located mainly outside of CpG islands and preferentially affected GTPase regulators and other cancer-related pathways.

Mechanism of action of lenalidomide in hematological malignancies.

Immunomodulatory drugs lenalidomide and pomalidomide are synthetic compounds derived by modifying the chemical structure of thalidomide to improve its potency and reduce its side effects. Lenalidomide is a 4-amino-glutamyl analogue of thalidomide that lacks the neurologic side effects of sedation and neuropathy and has emerged as a drug with activity against various hematological and solid malignancies. It is approved by FDA for clinical use in myelodysplastic syndromes with deletion of chromosome 5q and multiple myeloma.