A novel start-loss mutation of the SH2B3 gene in a family with myeloproliferative neoplasms.

The ever-increasing advances in high-throughput sequencing have broadened our understanding of the genetic pathogenesis of Philadelphia-negative myeloproliferative neoplasms (MPNs). Convergent studies have shown that MPN driver mutations associate with additional mutations found in genes coding for negative regulators of the JAK/STAT signaling, including the SH2B3 (SH2B-adaptor protein 3, also known as LNK). Here, we describe a novel heterozygous start-loss mutation of the SH2B3 gene (c.3G>A, SH2B3M? ) in a consanguineous family characterized by recurrent early onset of JAK2V617F -positive MPNs. The model represented by this pedigree suggests that the SH2B3 could be a predisposing mutation that facilitates the acquisition of driver mutations.

Nanoplastic impact on bone microenvironment: A snapshot from murine bone cells.

Our world is made of plastic. Plastic waste deeply affects our health entering the food chain. The degradation and/or fragmentation of plastics due to weathering processes result in the generation of nanoplastics (NPs). Only a few studies tested NPs effects on human health. NPs toxic actions are, in part, mediated by oxidative stress (OS) that, among its effects, affects bone remodeling. This study aimed to assess if NPs influence skeleton remodeling through OS. Murine bone cell cultures (MC3T3-E1 preosteoblasts, MLOY-4 osteocyte-like cells, and RAW264.7 pre-osteoclasts) were used to test the NPs detrimental effects on bone cells. NPs affect cell viability and induce ROS production and apoptosis (by caspase 3/7 activation) in pre-osteoblasts, osteocytes, and pre-osteoclasts. NPs impair the migration capability of pre-osteoblasts and potentiate the osteoclastogenesis of preosteoclasts. NPs affected the expression of genes related to inflammatory and osteoblastogenic pathways in pre-osteoblasts and osteocytes, related to the osteoclastogenic commitment of pre-osteoclasts. A better understanding of the impact of NPs on bone cell activities resulting in vivo in impaired bone turnover could give more information on the possible toxicity consequence of NPs on bone mass and the subsequent public health problems, such as bone disease.

Cordycepin (3'dA) Induces Cell Death of AC133+ Leukemia Cells via Re-Expression of WIF1 and Down-Modulation of MYC.

Wnt/ß-catenin signaling is critically required for the development and maintenance of leukemia stem cells (LSCs) in acute myeloid leukemia (AML) by constitutive activation of myeloid regeneration-related pathways. Cell-intrinsic activation of canonical Wnt signaling propagates in the nucleus by ß-catenin translocation, where it induces expression of target oncogenes such as JUN, MYC and CCND1. As the Wnt/ß-catenin pathway is now well established to be a key oncogenic signaling pathway promoting leukemic myelopoiesis, targeting it would be an effective strategy to impair LSC functionality. Although the effects of the adenosine analogue cordycepin in repressing ß-catenins and destabilizing the LSC niche have been highlighted, the cellular and molecular effects on AML-LSC have not been fully clarified. In the present study, we evaluated the potency and efficacy of cordycepin, a selective repressor of Wnt/ß-catenin signaling with anti-leukemia properties, on the AC133+ LSC fraction. Cordycepin effectively reduces cell viability of the AC133+ LSCs in the MUTZ-2 cell model and patient-derived cells through the induction of apoptosis. By Wnt-targeted RNA sequencing panel, we highlighted the re-expression of WIF1 and DKK1 among others, and the consequent downregulation of MYC and PROM1 (CD133) following MUTZ-2 cell exposure to increasing doses of cordycepin. Our results provide new insights into the molecular circuits involved in pharmacological inhibition mediated by cordycepin reinforcing the potential of targeting the Wnt/ß-catenin and co-regulatory complexes in AML.