A cAbl-MRTF-A Feedback Loop Contributes to Hepatic Stellate Cell Activation
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY
Authors: Lu, Yunjie; Lv, Fangqiao; Kong, Ming; Chen, Xuyang; Duen, Yunfei; Chen, Xuemin; Sun, Donglin; Fang, Mingming; Xu, Yong
Trans-differentiation of quiescent hepatic stellate cells (HSC) to myofibroblasts is a hallmark event in liver fibrosis. Previous studies have led to the discovery that myocardin-related transcription factor A (MRTF-A) is a key regulator of HSC trans-differentiation or, activation. In the present study we investigated the interplay between MRTFA and c-Abl (encoded by Abl1), a tyrosine kinase, in this process. We report that hepatic expression levels of c-Abl were down-regulated in MRTF-A knockout (KO) mice compared to wild type (WT) littermates in several different models of liver fibrosis. MRTFA deficiency also resulted in c-Abl down-regulation in freshly isolated HSCs from the fibrotic livers of mice. MRTF-A knockdown or inhibition repressed c-Abl in cultured HSCs in vitro. Further analyses revealed that MRTF-A directly bound to the Abl1 promoter to activate transcription by interacting with Sp1. Reciprocally, pharmaceutical inhibition of c-Abl suppressed MRTF-A activity. Mechanistically, c-Abl activated extracellular signal-regulated kinase (ERK), which in turn phosphorylated MRTF-A and promoted MRTF-A nuclear trans-localization. In conclusion, our data suggest that a c-Abl-MRTF-A positive feedback loop contributes to HSC activation and liver fibrosis.
Better survivals in adolescent and Young adults, compared to adults with acute lymphoblastic leukemia - A multicenter prospective registry in Thai population
Authors: Limvorapitak, Wasithep; Owattanapanich, Weerapat; Utchariyaprasit, Eakkapol; Niparuck, Pimjai; Puavilai, Teeraya; Tantiworawit, Adisak; Rattanathammethee, Thanawat; Saengboon, Supawee; Sriswasdi, Chantarapa; Julamanee, Jakrawadee; Saelue, Piroon; Polprasert, Chantana; Wudhikarn, Kitsada; Wanitpongpun, Chinadol; Prayongratana, Kannadit
Adult acute lymphoblastic leukemia (ALL) is an uncommon hematologic malignancy with high relapse and mortality rate. This study aimed to describe characteristics and outcomes of Thai ALL patients, and to determine the differences between adolescent and young adult (AYA) and adult ALL. ALL patients aged > 15 years were prospectively enrolled from 2015 to 2017. AYA patients were defined as age <= 39 years. Out of the 188 enrolled ALL patients, 9 were excluded due to changes in diagnosis or incomplete data. From the remaining 179 patients, 103 (57.5%) were AYA and 76 (42.5%) were adult. AYA ALL patients were predominantly male, had higher T-cell phenotype, higher white blood cells and hemoglobin, with lower frequency of Philadelphia chromosome or BCR-ABL1 mutation. All patients received treatment by adult hematologist, however 40.8% of AYA ALL patients were treated with pediatric adapted protocol. The effects of stem cell transplantation (SCT) and age were determined by stratified patients as: AYA - no SCT 91 (51.1%), AYA - SCT 12 (6.7%), adult - no SCT 64 (36.0%) and adult - SCT 11 (6.2%). The 2-year overall survival were: 53.9%, 60.6%, 39.2% and 70.1%, respectively. The 2-year event-free survival were: 45.0%, 54.0%, 21.0% and 49.9%, respectively. This is a large multicenter ALL cohort study conducted in Thailand. Patients who underwent SCT showed significantly improved OS and EFS, confirming the benefit of graft-versus-leukemia effect in ALL. However, further studies with longer follow-up, expanded use of SCT, use of molecular data, and minimal residual disease status are warranted.