Polycomb Factor PHF19 Controls Cell Growth and Differentiation Toward Erythroid Pathway in Chronic Myeloid Leukemia Cells.

Polycomb group (PcG) of proteins are a group of highly conserved epigenetic regulators involved in many biological functions, such as embryonic development, cell proliferation, and adult stem cell determination. PHD finger protein 19 (PHF19) is an associated factor of Polycomb repressor complex 2 (PRC2), often upregulated in human cancers. In particular, myeloid leukemia cell lines show increased levels of PHF19, yet little is known about its function. Here, we have characterized the role of PHF19 in myeloid leukemia cells. We demonstrated that PHF19 depletion decreases cell proliferation and promotes chronic myeloid leukemia (CML) differentiation. Mechanistically, we have shown how PHF19 regulates the proliferation of CML through a direct regulation of the cell cycle inhibitor p21. Furthermore, we observed that MTF2, a PHF19 homolog, partially compensates for PHF19 depletion in a subset of target genes, instructing specific erythroid differentiation. Taken together, our results show that PHF19 is a key transcriptional regulator for cell fate determination and could be a potential therapeutic target for myeloid leukemia treatment.

The Polycomb-associated factor PHF19 controls hematopoietic stem cell state and differentiation.

Adult hematopoietic stem cells (HSCs) are rare multipotent cells in bone marrow that are responsible for generating all blood cell types. HSCs are a heterogeneous group of cells with high plasticity, in part, conferred by epigenetic mechanisms. PHF19, a subunit of the Polycomb repressive complex 2 (PRC2), is preferentially expressed in mouse hematopoietic precursors. Here, we now show that, in stark contrast to results published for other PRC2 subunits, genetic depletion of Phf19 increases HSC identity and quiescence. While proliferation of HSCs is normally triggered by forced mobilization, defects in differentiation impede long-term correct blood production, eventually leading to aberrant hematopoiesis. At molecular level, PHF19 deletion triggers a redistribution of the histone repressive mark H3K27me3, which notably accumulates at blood lineage-specific genes. Our results provide novel insights into how epigenetic mechanisms determine HSC identity, control differentiation, and are key for proper hematopoiesis.

Radial optic neurotomy in central retinal vein occlusion: comparison of outcome in younger vs older patients.

PURPOSE: To evaluate the effectiveness of radial optic neurotomy (RON) for central retinal vein occlusion (CRVO) in patients < or =50 years of age (group 1) vs those >50 (group 2). DESIGN: Prospective, interventional, comparative case series. METHODS: The study included 43 consecutive patients with CRVO and preoperative visual acuity (VA) < or =0.70 logarithm of minimal angle of resolution (logMAR). All patients underwent pars plana vitrectomy and RON at the nasal border of the optic disk. VA and optical coherence tomography (OCT) findings were recorded preoperatively and at one, six, and 12 months postoperatively. RESULTS: Systemic hypertension, diabetes, and open-angle glaucoma were statistically significantly more prevalent in group 2 (P < .05). One patient in group 1 had hyperhomocysteinemia, and had another antiphospholipid syndrome. Fifty percent of patients in group 1 gained > or =3 lines of Early Treatment Diabetic Retinopathy Study (ETDRS) vision, vs 33% in group 2. Mean final VA was 0.5 logMAR VA in group 1 vs 0.8 in group 2 (P = .04). Foveal thickness decreased significantly in both groups (P < .001). Ten patients (55.6%) in group 1 and 13 (54.2%) in group 2 developed retinochoroidal collaterals. CONCLUSIONS: Underlying systemic disease does not seem to be an important factor in the pathogenesis of CRVO in younger patients, and thrombophilia was present in only 11% of patients in this age group. RON yielded better functional results in younger patients, although functional improvement remained limited in those with low baseline VA.

Pre-clinical evaluation of small molecule LOXL2 inhibitors in breast cancer.

Lysyl Oxidase-like 2 (LOXL2), a member of the lysyl oxidase family of amine oxidases is known to be important in normal tissue development and homeostasis, as well as the onset and progression of solid tumors. Here we tested the anti-tumor properties of two generations of novel small molecule LOXL2 inhibitor in the MDA-MB-231 human model of breast cancer. We confirmed a functional role for LOXL2 activity in the progression of primary breast cancer. Inhibition of LOXL2 activity inhibited the growth of primary tumors and reduced primary tumor angiogenesis. Dual inhibition of LOXL2 and LOX showed a greater effect and also led to a lower overall metastatic burden in the lung and liver. Our data provides the first evidence to support a role for LOXL2 specific small molecule inhibitors as a potential therapy in breast cancer.