Fms-like tyrosine kinase 3 (FLT3) mutation is one of the most common mutations in acute myeloid leukemia (AML). However, the effect of FLT3 mutation on survival is currently still controversial and the leukemogenic mechanisms are still under further investigation. The aim of our study is to identify differentially expressed genes (DEGs) in FLT3-mutant AML and to find crucial DEGs whose expression level is related to prognosis for further analysis. By mining the TCGA-LAML dataset, 619 differentially expressed lncRNAs (DElncRNAs) and 1,428 differentially expressed mRNAs (DEmRNAs) were identified between FLT3-mutant and FLT3-wildtype samples. Through weighted gene correlation network analysis (WGCNA) and the following Cox proportional hazards regression analysis, we constructed the prognostic risk models to identify the hub DElncRNAs and DEmRNAs associated with AML prognosis. The presence of both SH3TC2 divergent transcript (SH3TC2-DT) and SH3TC2 in respective prognostic risk models promotes us to further study the significance of this gene pair in AML. SH3TC2-DT and SH3TC2 were identified to be coordinately high expressed in FLT3-mutant AML samples. High expression of this gene pair was associated with poor survival. Using logistic regression analysis, we found that high SH3TC2-DT/SH3TC2 expression was associated with FLT3 mutation, high WBC count, and intermediate cytogenetic and molecular-genetic risk. AML with SH3TC2-DT/SH3TC2 high expression showed enrichment of transcripts associated with stemness, quiescence, and leukemogenesis. Our study suggests that the SH3TC2-DT/SH3TC2 gene pair may be a possible biomarker to further optimize AML prognosis and may function in stemness or quiescence of FLT3-mutant leukemic stem cells (LSCs).

e15028 Background: The chimeric antigen receptor (CAR) T cell treatment has been demonstrated as an effective therapy to treat relapsed/refractory B cell malignancy. However, tumor microenvironment influences and affects the efficacy of CAR T treatment. For example, programmed death ligand 1/2 (PDL1/2) may inhibit the CAR T cells via interaction with up-regulated programmed cell death protein 1 (PD1) after T cells activation, suppressing the tumor-killing capability of the CAR T cells. Thus, blockade of the PD1-PDL1/2 interaction may enhance the anti-tumor efficacy of CAR T therapy. Methods: Here, we generated CAR T expressed an anti-CD19 CAR molecule and a dominant-negative PD1 molecule. Compared with conventional CART cells, these “armored” CART cells showed the enhanced capability of tumor-killing and more “memory-like” phenotypes after multiple-round tumor challenging. These results suggest dominant-negative PD1 molecules may protect CART cells from exhaustion in the tumor microenvironment. Results: Further, we reported the findings of a clinical trial for six relapsed or refractory B-cell non-Hodgkin lymphoma (NHLs) patients treated using our armored CAR T cells. These six patients failed multiple rounds of chemotherapy and radiotherapy. In the clinical trial, the patients were infused with autologous CAR T cells range from1×106/kg to 8×106/kg. PET/CT showed significant tumor shrinkage and SUV max declines in all six patients, and the ongoing responses were monitored. The best overall response rate (ORR)was 100%. Conclusions: The results of these six patients in the clinical trial showed that our armored CAR T cells achieved the significant anti-bulky lymphoma response while causing limited and tolerated cytokine release syndrome and central nervous system toxicity. Thus, dominant-negative PD1 molecules may increase CAR T cells persistence in patients, enhancing the efficacy of CAR T cells for treating blood cancer. Finally, dominant-negative PD1 can be used as a platform technology and may be applied to other adoptive cellular immunotherapies such as TCR-T or TIL in the treatment of solid tumors. We are continuing to monitor current patients and recruit more patients for the clinical trial.

Objective Diffuse large B-cell lymphoma (DLBCL) is an aggressive type of non-Hodgkin lymphoma. Due to its genetic heterogeneity and abnormal metabolism, many DLBCL patients have a poor prognosis. This study investigated the key metabolism-related genes and potential mechanisms. Methods Differentially expressed genes, differentially expressed transcription factors (TFs), and differentially expressed metabolism-related genes (DEMRGs) of glucose and lipid metabolic processes were identified using the edgeR package. Key DEMRGs were screened by Lasso regression, and a prediction model was constructed. The cell type identification by estimating relative subsets of RNA transcripts algorithm was utilized to assess the fraction of immune cells, and Gene Set Enrichment Analysis was used to determine immune-related pathways. A regulatory network was constructed with significant co-expression interactions among TFs, DEMRGs, immune cells/pathways, and hallmark pathways. Results A total of 1551 DEMRGs were identified. A prognostic model with a high applicability (area under the curve=0.921) was constructed with 13 DEMRGs. Tumorigenesis of DLBCL was highly related to the neutrophil count. Four DEMRGs (PRXL2AB, CCN1, DECR2 and PHOSPHO1) with 32 TF—DEMRG, 36 DEMRG—pathway, 14 DEMRG—immune-cell, 9 DEMRG—immune-gene-set, and 67 DEMRG—protein-chip interactions were used to construct the regulatory network. Conclusion We provided a prognostic prediction model based on 13 DEMRGs for DLBCL. We found that phosphatase, orphan 1 (PHOSPHO1) is positively regulated by regulatory factor X5 (RFX5) and mediates MYC proto-oncogene (MYC) targeting the V2 pathway and neutrophils.

The seven trans-membrane spanning G protein couple receptors(GPCRs) constitute the largest family of FDA approved drug targets to treat numerous human diseases, including metabolic associated disorders. The Melanocortin Receptor Accessory Protein 2 (MRAP2), a small single transmembrane protein broadly expressed in multiple tissues has been defined as a vital endocrine pivot of five melanocortin receptors(MC1R-MC5R) and several other GPCRs in the regulation of central neuronal appetite and peripheral energy homeostasis. However, MRAP2 null mouse model exhibited late onset obesity syndrome without alteration on the eating behavior, a huge phenotypic departure from MC4R KO animals. In this study, we identified GLP1R and MCHR1, the two energy regulators as novel GPCR targets and characterized the specific regions of MRAP2 protein that required for the pharmacological modulation of the intracellular cAMP cascades. The simultaneous inhibitory effect of MRAP2 on the anorectic GLP1R and orectic MCHR1 signaling further elucidated the complex endocrine network of GPCR signaling which may explain the composite metabolic phenotypes of MRAP2 deficiency.

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