Decreased zinc-fingers and homeoboxes family expression was associated with unfavorable outcomes and immune infiltration in lung adenocarcinoma.

Background: The zinc-fingers and homeoboxes (ZHX) family is a group of nuclear homodimeric transcriptional repressors that play an essential role in developing and progressing diverse malignancies. However, the association of ZHX family expression with prognosis and immune infiltration in lung adenocarcinoma (LUAD) is still unclear. The current study aimed to investigate the relationship between ZHX family expression and clinical outcomes and immune infiltration in LUAD patients. Methods: ZHXs family expression was determined by using the Oncomine database and Cancer Cell Line Encyclopedia (CCLE). The impact of ZHXs family expression on prognosis was analyzed by using the Kaplan-Meier-plotter online database. The Search Tool for the Retrieval of Interacting Genes (STRING) database was utilized to construct the interaction network based on the selected differentially expressed genes associated with ZHXs. The Database for Annotation, Visualization, and Integrated Discovery (DAVID) was used to perform the enrichment of the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways. The functional state of the ZHXs family in diverse types of malignancies was determined by CancerSEA. The Tumor Immune Estimation Resource (TIMER) database was used to evaluate the association of the ZHXs family with immune cell infiltrates. ZHXs family expression was validated by the Gene Expression Omnibus (GEO) database and real-time polymerase chain reaction (RT-PCR) in 10 paired tumors and normal tissues. Results: ZHX1-3 expression level significantly decreased in LUAD compared with normal tissues. Attenuated ZHXs expression was significantly associated with unfavorable overall survival in LUAD patients. ZHX family members were positively associated with immune infiltration of monocytes, tumor-associated macrophages (TAMs), M1 and M2 macrophages in LUAD. ZHX family expression was also significantly related to a variety of immune marker sets in LUAD. GEO analysis and RT-PCR validated the significant decrease of ZHXs expression level in LUAD. Conclusions: The current study revealed that ZHX family expression was significantly correlated with unfavorable outcomes and immune infiltration in LUAD. The findings herein provide a promising basis for further study into the potential biological function of the ZHX family in LUAD and lay a foundation for developing therapeutic targets for LUAD patients.

Genomic landscape of CD34+ hematopoietic cells in myelodysplastic syndrome and gene mutation profiles as prognostic markers.

Myelodysplastic syndrome (MDS) includes a group of diseases characterized by dysplasia of bone marrow myeloid lineages with ineffective hematopoiesis and frequent evolution to acute myeloid leukemia (AML). Whole-genome sequencing was performed in CD34(+) hematopoietic stem/progenitor cells (HSPCs) from eight cases of refractory anemia with excess blasts (RAEB), the high-risk subtype of MDS. The nucleotide substitution patterns were found similar to those reported in AML, and mutations of 96 protein-coding genes were identified. Clonal architecture analysis revealed the presence of subclones in six of eight cases, whereas mutation detection of CD34(+) versus CD34(-) cells revealed heterogeneity of HSPC expansion status. With 39 marker genes belonging to eight functional categories, mutations were analyzed in 196 MDS cases including mostly RAEB (n = 89) and refractory cytopenia with multilineage dysplasia (RCMD) (n = 95). At least one gene mutation was detected in 91.0% of RAEB, contrary to that in RCMD (55.8%), suggesting a higher mutational burden in the former group. Gene abnormality patterns differed between MDS and AML, with mutations of activated signaling molecules and NPM1 being rare, whereas those of spliceosome more common, in MDS. Finally, gene mutation profiles also bore prognostic value in terms of overall survival and progression free survival.

Iqcg is essential for sperm flagellum formation in mice.

Mammalian spermatogenesis comprises three successive phases: mitosis phase, meiosis phase, and spermiogenesis. During spermiogenesis, round spermatid undergoes dramatic morphogenesis to give rise to mature spermatozoon, including the condensation and elongation of nucleus, development of acrosome, formation of flagellum, and removal of excessive cytoplasm. Although these transformations are well defined at the morphological level, the mechanisms underlying these intricate processes are largely unknown. Here, we report that Iqcg, which was previously characterized to be involved in a chromosome translocation of human leukemia, is highly expressed in the spermatogenesis of mice and localized to the manchette in developing spermatids. Iqcg knockout causes male infertility, due to severe defects of spermiogenesis and resultant total immobility of spermatozoa. The axoneme in the Iqcg knockout sperm flagellum is disorganized and hardly any typical ("9+2") pattern of microtubule arrangement could be found in Iqcg knockout spermatids. Iqcg interacts with calmodulin in a calcium dependent manner in the testis, suggesting that Iqcg may play a role through calcium signaling. Furthermore, cilia structures in the trachea and oviduct, as well as histological appearances of other major tissues, remain unchanged in the Iqcg knockout mice, suggesting that Iqcg is specifically required for spermiogenesis in mammals. These results might also provide new insights into the genetic causes of human infertility.

Functional and molecular features of the calmodulin-interacting protein IQCG required for haematopoiesis in zebrafish.

We previously reported a fusion protein NUP98-IQCG in an acute leukaemia, which functions as an aberrant regulator of transcriptional expression, yet the structure and function of IQCG have not been characterized. Here we use zebrafish to investigate the role of iqcg in haematopoietic development, and find that the numbers of haematopoietic stem cells and multilineage-differentiated cells are reduced in iqcg-deficient embryos. Mechanistically, IQCG binds to calmodulin (CaM) and acts as a molecule upstream of CaM-dependent kinase IV (CaMKIV). Crystal structures of complexes between CaM and IQ domain of IQCG reveal dual CaM-binding footprints in this motif, and provide a structural basis for a higher CaM-IQCG affinity when deprived of calcium. The results collectively allow us to understand IQCG-mediated calcium signalling in haematopoiesis, and propose a model in which IQCG stores CaM at low cytoplasmic calcium concentrations, and releases CaM to activate CaMKIV when calcium level rises.