Genomic landscapes of 92 adult and 111 pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL) were investigated using next-generation sequencing and copy number alteration analysis. Recurrent gene mutations and fusions were tested in an additional 87 adult and 93 pediatric patients. Among the 29 newly identified in-frame gene fusions, those involving MEF2D and ZNF384 were clinically relevant and were demonstrated to perturb B-cell differentiation, with EP300-ZNF384 inducing leukemia in mice. Eight gene expression subgroups associated with characteristic genetic abnormalities were identified, including leukemia with MEF2D and ZNF384 fusions in two distinct clusters. In subgroup G4 which was characterized by ERG deletion, DUX4-IGH fusion was detected in most cases. This comprehensive dataset allowed us to compare the features of molecular pathogenesis between adult and pediatric B-ALL and to identify signatures possibly related to the inferior outcome of adults to that of children. We found that, besides the known discrepancies in frequencies of prognostic markers, adult patients had more cooperative mutations and greater enrichment for alterations of epigenetic modifiers and genes linked to B-cell development, suggesting difference in the target cells of transformation between adult and pediatric patients and may explain in part the disparity in their responses to treatment.

Background: The new coronavirus pneumonia (NCP) is now causing a severe public health emergency. The novel coronavirus 2019 (2019-nCoV) infected individuals by binding human angiotensin converting enzyme II (ACE2) receptor. ACE2 is widely expressed in multiple organs including respiratory, cardiovascular, digestive and urinary systems in healthy individuals. These tissues with high expression level of ACE2 seemed to be more vulnerable to SARS-CoV-2 infection. Recently, it has been reported that patients with tumors were likely to be more susceptible to SARS-CoV-2 infection and indicated poor prognosis. Methods:The tissue atlas database and the blood atlas were used to analyze the distribution of ACE2 in human tissues or organs of cancers and normal samples. Starbase dataset was applied to predict the prognosis of cancers according to expression level of ACE2.Results: In this study, we demonstrated a landscape profiling analysis on expression level of ACE2 in pancancers and showed the risky of different type of cancers to SARS-CoV-2 according to the expression level of ACE2. In addition, we found that ACE2 was both differential expression and related to the prognosis only in liver hepatocellular carcinoma (LIHC). Relative high expression of ACE2 indicated a favorable prognosis in LIHC, but they might be more susceptible to SARS-CoV-2. Conclusions:We indeed emphasized that LIHC patients with high expression level of ACE2 should be more cautious of the virus infection. Our study might provide a potential clue for preventing infection of SARS-CoV-2 in cancers.

Cancer stem cells (CSCs) are characterized by self‐renewal and ‐differential potential as compared to common cancer cells and play an important role in the development and therapeutic resistance of liver hepatocellular carcinoma (LIHC). However, the specific pathogenesis of LIHC stem cells is still unclear, and the genes involved in the stemness of LIHC stem cells are currently unknown. In this study, we investigated novel biomarkers associated with LIHC and explored the expression characteristics of stem cell‐related genes in LIHC. We found that mRNA expression‐based stemness index (mRNAsi) was significantly overexpressed in liver cancer tissues. Further, mRNAsi expression in LIHC increased with the tumor pathological grade, with grade 4 tumors harboring the greatest stem cell features. Upon establishing mRNAsi scores based on mRNA expression of every gene, we found an association with poor overall survival in LIHC. Moreover, modules of interest were determined based on weighted gene co‐expression network analysis (WGCNA) inclusion criteria, and three significant modules (red, green, and brown) and 21 key genes (DCN, ECM1, HAND2, PTGIS, SFRP1, SRPX, COLEC10, GRP182, ADAMTS7, CD200, CDH11, COL8A1, FAP, LZTS1, MAP1B, NAV1, NOTCH3, OLFML2A, PRR16, TMEM119, and VCAN) were identified. Functional analysis of these 21 genes demonstrated their enrichment in pathways involved in angiogenesis, negative regulation of DNA‐binding transcription factor activity, apoptosis, and autophagy. Causal relationship with proteins indicated that the Wnt, Notch, and Hypoxia pathways are closely related to LIHC tumorigenesis. To our knowledge, this is the first report of a novel CSC biomarker, mRNAsi, to predict the prognosis of LIHC. Further, we identified 21 key genes through mRNA expression network analysis, which could be potential therapeutic targets to inhibit the stemness of cancer cells in LIHC.

The gene encoding DNA methyltransferase 3A (DNMT3A) is mutated in ∼20% of acute myeloid leukemia cases, with Arg882 (R882) as the hotspot. Here, we addressed the transformation ability of the DNMT3A-Arg882His (R882H) mutant by using a retroviral transduction and bone marrow transplantation (BMT) approach and found that the mutant gene can induce aberrant proliferation of hematopoietic stem/progenitor cells. At 12 mo post-BMT, all mice developed chronic myelomonocytic leukemia with thrombocytosis. RNA microarray analysis revealed abnormal expressions of some hematopoiesis-related genes, and the DNA methylation assay identified corresponding changes in methylation patterns in gene body regions. Moreover, DNMT3A-R882H increased the CDK1 protein level and enhanced cell-cycle activity, thereby contributing to leukemogenesis.genomic variation | epigenetic abnormality | leukemogenic effect D NA methylation represents one of the major epigenetic modifications and plays a key role in a number of regulatory mechanisms of life processes (1-3). In mammals, the executors of genome methylation are members of the DNA methyltransferase (DNMT) family, including DNMT1, DNMT3A and DNMT3B. It has been well established that DNMT3A forms complex with DNMT3L to catalyze the de novo DNA methylation (4, 5). Both DNMT3A and DNMT3B show high expression levels at the early embryogenesis, and their expressions are down-regulated along with the embryonic development and cell differentiation (6, 7).It is well known that all blood-cell lineages originate from the multipotent hematopoietic stem cells (HSCs). A number of regulations are involved in directing HSCs activities, and the epigenetic modifications are of great importance (8,9). It has been shown that loss of Dnmt3a in a Dnmt3a-conditional knockout mouse results in progressive impairment of HSCs differentiation and expansion (10). Notably, DNMT3A recently has been reported to be mutated in up to 20% of cases of acute myeloid leukemia (AML), mostly in cases with monocytic lineage (AML-M5 or -M4) and clinical features including old age, normal karyotype, leukocytosis and thrombocytosis, and poor prognosis (11,12). Although a variety of DNMT3A mutations have been identified, the majority (∼50%) affect Arg882 (R882) located at the catalytic domain, and the most common substitution is Arg882His (R882H) (11,13,14). It also has been suggested that R882 mutation may interfere with oligomerization of DNMT3A and thereby exert an aberrant effect on its enzymatic function (15). Evidence has been obtained supporting DNMT3A mutations as the fundamental genetic event at the initiation stage of AML pathogenesis (16,17). However, the in vivo transformation power of DNMT3A mutations needs to be addressed, and the relevant molecular and cellular mechanisms of these mutations in AML pathogenesis remain obscure.In the present work, using retroviral transduction and bone marrow transplantation (BMT) technology, we were able to investigate the in vivo effect of the DNMT3A-R882H mutation on the transforming po...