Qianying Pan

The progression of multiple myeloma (MM) is governed by a network of molecular signals, the majority of which remain to be identified. Recent studies suggest that Runt-related transcription factor 2 (Runx2), a well-known bone-specific transcription factor, is also expressed in solid tumors, where expression promotes both bone metastasis and osteolysis. However, the function of Runx2 in MM remains unknown. The current study demonstrated that (1) Runx2 expression in primary human MM cells is significantly greater than in plasma cells from healthy donors and patients with monoclonal gammopathy of undetermined significance; (2) high levels of Runx2 expression in MM cells are associated with a high-risk population of MM patients; and (3) overexpression of Runx2 in MM cells enhanced tumor growth and disease progression in vivo. Additional studies demonstrated that MM cell-derived Runx2 promotes tumor progression through a mechanism involving the upregulation of Akt/β-catenin/Survivin signaling and enhanced expression of multiple metastatic genes/proteins, as well as the induction of a bone-resident cell-like phenotype in MM cells. Thus, Runx2 expression supports the aggressive phenotype of MM and is correlated with poor prognosis. These data implicate Runx2 expression as a major regulator of MM progression in bone and myeloma bone disease.

// Juan Li 1, 2, * , Qianying Pan 1, 2, * , Patrick D. Rowan 1, * , Timothy N. Trotter 1 , Deniz Peker 1 , Kellie M. Regal 1 , Amjad Javed 3, 4 , Larry J. Suva 5 , Yang Yang 1, 3 1 Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA 2 Department of Hematology, the First Affiliated Hospital of Sun Yat-Sen University, Guangdong, China 3 Comprehensive Cancer Center and the Center for Metabolic Bone Disease, University of Alabama at Birmingham, Birmingham, AL, USA 4 Department of Oral and Maxillofacial Surgery, School of Dentistry, University of Alabama at Birmingham, Birmingham, AL, USA 5 Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A & M University, College Station, TX, USA * These authors contributed equally to this work Correspondence to: Yang Yang, e-mail: yangyang@uab.edu Keywords: multiple myeloma, bone dissemination, heparanase, mesenchymal marker, tumor microenvironment Received: June 19, 2015      Accepted: January 21, 2016      Published: February 03, 2016 ABSTRACT Bone dissemination and bone disease occur in approximately 80% of patients with multiple myeloma (MM) and are a major cause of patient mortality. We previously demonstrated that MM cell-derived heparanase (HPSE) is a major driver of MM dissemination to and progression in new bone sites. However the mechanism(s) by which HPSE promotes MM progression remains unclear. In the present study, we investigated the involvement of mesenchymal features in HPSE-promoted MM progression in bone. Using a combination of molecular, biochemical, cellular, and in vivo approaches, we demonstrated that (1) HPSE enhanced the expression of mesenchymal markers in both MM and vascular endothelial cells; (2) HPSE expression in patient myeloma cells positively correlated with the expression of the mesenchymal markers vimentin and fibronectin. Additional mechanistic studies revealed that the enhanced mesenchymal-like phenotype induced by HPSE in MM cells is due, at least in part, to the stimulation of the ERK signaling pathway. Finally, knockdown of vimentin in HPSE expressing MM cells resulted in significantly attenuated MM cell dissemination and tumor growth in vivo . Collectively, these data demonstrate that the mesenchymal features induced by HPSE in MM cells contribute to enhanced tumor cell motility and bone-dissemination.

Y-autosomal translocation has been previously reported in association with male infertility; however, the mechanisms of Y-autosomal translocation and non‑obstructive azoospermia or severe oligospermia remain unclear. G‑banding and fluorescence in situ hybridization (FISH) were performed to analyze the translocation of chromosomes, and a single nucleotide polymorphism (SNP) genotyping assay was used to test mutations. The present study describes three new cases with a de novo balanced translocation t(Y;13), t(Y;9) and t(Y;6). To further explore the genotype‑phenotype correlation, G‑banding and FISH were performed and indicated the presence of a derivative chromosome. The SNP genotyping assay using a microarray revealed no abnormality, especially in the Y chromosome. Molecular deletion analysis demonstrated that no microdeletion was detected in the azoospermia factor region of the Y chromosome in the examined, infertile men. Based on these observations, the authors proposed the hypothesis that a position effect involving unknown spermatogenesis regulatory gene(s) serves a key role in male infertility.

Objectives Compared with the 3 + 7 regimen, the cladribine-containing regimen has led to improvements in the rate of complete remission (CR) in the treatment of newly diagnosed acute myeloid leukemia (AML) patients. We conducted a systematic review and meta-analysis to investigate the overall efficacy and safety of cladribine-containing regimens in the induction treatment of newly diagnosed AML patients.Methods Eligible studies were identified from the PubMed, EMBASE, and Cochrane Library databases. Efficacy was assessed by CR rate, disease-free survival (DFS), and overall survival (OS). Safety was evaluated based on the early death (ED) rate, days for neutrophils<0.5 × 109/L, days for platelets<50 × 109/L, and duration of hospital stay after treatment.Results A total of 14 clinical trials were included in this meta-analysis, enrolling a total of 1058 newly diagnosed AML patients. The pooled estimate with a 95% confidence interval (CI) for CR was 64% (95% CI: 58–70%). Compared with the control group, the CR rate of the cladribine-containing regimen was higher (OR was 1.92 (95% CI: 1.55–2.38)). The combined ED rate was estimated to be 10% (95% CI: 5–14%). Compared with the control group, the ED rate of the cladribine-containing regimen was not increased (OR was 1.09 (95% CI: 0.78–1.53)).Conclusion This meta-analysis suggests that cladribine-containing regimens are likely to be effective and safe for induction treatment of newly diagnosed AML patients. However, large sample size and prospective controlled studies are needed to confirm our findings.