Nod1-dependent NF-kB activation initiates hematopoietic stem cell specification in response to small Rho GTPases.

Uncovering the mechanisms regulating hematopoietic specification not only would overcome current limitations related to hematopoietic stem and progenitor cell (HSPC) transplantation, but also advance cellular immunotherapies. However, generating functional human induced pluripotent stem cell (hiPSC)-derived HSPCs and their derivatives has been elusive, necessitating a better understanding of the developmental mechanisms that trigger HSPC specification. Here, we reveal that early activation of the Nod1-Ripk2-NF-kB inflammatory pathway in endothelial cells (ECs) primes them to switch fate towards definitive hemogenic endothelium, a pre-requisite to specify HSPCs. Our genetic and chemical embryonic models show that HSPCs fail to specify in the absence of Nod1 and its downstream kinase Ripk2 due to a failure on hemogenic endothelial (HE) programming, and that small Rho GTPases coordinate the activation of this pathway. Manipulation of NOD1 in a human system of definitive hematopoietic differentiation indicates functional conservation. This work establishes the RAC1-NOD1-RIPK2-NF-kB axis as a critical intrinsic inductor that primes ECs prior to HE fate switch and HSPC specification. Manipulation of this pathway could help derive a competent HE amenable to specify functional patient specific HSPCs and their derivatives for the treatment of blood disorders.

Evaluation of plasma Epstein-Barr virus DNA as a biomarker for Epstein-Barr virus-associated Hodgkin lymphoma.

OBJECTIVES: Epstein-Barr virus is a tumorigenic virus and has been extensively studied as a causative agent for Hodgkin lymphoma. Although immunostaining of the tumor biopsy is the standard method for diagnosis of Epstein-Barr virus-driven Hodgkin lymphoma, the invasiveness of the procedure renders it difficult and less desirable for the patients. Therefore, we designed this study to evaluate the efficiency of plasma Epstein-Barr virus DNA detection as an alternative diagnostic and prognostic method for Epstein-Barr virus-associated Hodgkin lymphoma. METHODS: This analytical cross-sectional study was conducted during March 2017 to December 2018 including 43 Hodgkin lymphoma patients diagnosed histopathologically followed by the latent membrane protein-1 immunohistochemistry to determine their Epstein-Barr virus association. Plasma Epstein-Barr virus DNA in these samples was measured using quantitative polymerase chain reaction (qPCR). RESULTS: Of total, 29 (67.44%) patients tested positive for plasma Epstein-Barr virus DNA. On comparing results of latent membrane protein-1 immunohistochemistry (IHC) with plasma Epstein-Barr virus DNA, plasma Epstein-Barr virus DNA was found in 25 of 30 patients with latent membrane protein-1 expression and 4 of 13 patients without latent membrane protein-1 expression. The sensitivity and the specificity of plasma Epstein-Barr virus DNA detection with respect to latent membrane protein-1 IHC were found to be 83.33% and 69.23%, respectively (p = 0.0014). CONCLUSION: Determination of plasma Epstein-Barr virus DNA was found to be highly sensitive and specific in characterizing Epstein-Barr virus-associated Hodgkin lymphoma, suggesting that this diagnostic method holds promise as an alternative and more convenient method of diagnosis compared with tissue biopsy.