Mice expressing a transgene encoding the transcription factor NF-E2 in hematopoietic cells exhibit features of myeloproliferative neoplasms, including thrombocytosis, Epo-independent colony formation, stem and progenitor cell overabundance, leukocytosis, and progression to acute myeloid leukemia.

We have previously described novel histone acetyltransferase (HAT) inhibitors that block neuroblastoma cell growth in vitro. Here we show that two selected pyridoisothiazolone HAT inhibitors, PU139 and PU141, induce cellular histone hypoacetylation and inhibit growth of several neoplastic cell lines originating from different tissues. Broader in vitro selectivity profiling shows that PU139 blocks the HATs Gcn5, p300/CBP-associated factor (PCAF), CREB (cAMP response element-binding) protein (CBP) and p300, whereas PU141 is selective toward CBP and p300. The pan-inhibitor PU139 triggers caspase-independent cell death in cell culture. Both inhibitors block growth of SK-N-SH neuroblastoma xenografts in mice and the PU139 was shown to synergize with doxorubicin in vivo. The latter also reduces histone lysine acetylation in vivo at concentrations that block neoplastic xenograft growth. This is one of the very few reports on hypoacetylating agents with in vivo anticancer activity.

Mutations in the transcription factor NF-E2 in patients with myeloproliferative neoplasms result in a truncated protein that enhances the function of wild-type NF-E2 and causes erythrocytosis and throbocytosis in a mouse model.

The transcription factor "nuclear factor erythroid 2" (NFE2) is overexpressed in the majority of patients with myeloproliferative neoplasms (MPNs). In murine models, elevated NFE2 levels cause an MPN phenotype with spontaneous leukemic transformation. However, both the molecular mechanisms leading to NFE2 overexpression and its downstream targets remain incompletely understood. Here, we show that the histone demethylase constitutes a novel NFE2 target gene. JMJD1C levels are significantly elevated in polycythemia vera (PV) and primary myelofibrosis patients; concomitantly, global H3K9me1 and H3K9me2 levels are significantly decreased. JMJD1C binding to the promoter is increased in PV patients, decreasing both H3K9me2 levels and binding of the repressive heterochromatin protein-1α (HP1α). Hence, JMJD1C and NFE2 participate in a novel autoregulatory loop. Depleting JMJD1C expression significantly reduced cytokine-independent growth of an MPN cell line. Independently, NFE2 is regulated through the epigenetic JAK2 pathway by phosphorylation of H3Y41. This likewise inhibits HP1α binding. Treatment with decitabine lowered H3Y41ph and augmented H3K9me2 levels at the locus in HEL cells, thereby increasing HP1α binding, which normalized NFE2 expression selectively in JAK2-positive cell lines.

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© Ferrata Storti Foundationorganelles as well as the cell nucleus. 4 Elimination of organelles like ribosomes and mitochondria, called autophagy in general, or more specifically ribophagy and mitophagy, respectively, is an essential step in the maturation of reticulocytes to erythrocytes.

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In order to assess the potential of Spirulina (Arthospira) platensis as a source of abundant, thermostable nitrate assimilatory enzymes, the specific activities and thermal tolerance of nitrate reductase (NR), nitrite reductase (NiR) and glutamine synthetase (GS) were compared with those of rice in crude extracts in vitro. The results show that Spirulina enzymes have relatively higher thermotolerance. When the extracts were pre-exposed to 80 °C for 1 hr, Spirulina enzymes retained higher activities by 3.4, 1.7 and 3.7 fold, respectively than corresponding enzymes in rice. This property was not due to salts and other small proteins/molecules, as their removal by gel filtration (G-25) did not affect their thermotolerance.