IKZF3/Aiolos H195Y mutation identified in a mouse model of B cell leukemia results in altered DNA binding and altered STAT5-dependent gene expression.

Precursor B cell acute lymphoblastic leukemia (Pre-B-ALL) arises from developing B cells and frequently involves mutations in genes encoding transcription factors. In this study, we investigated the function of mutations in the transcription factor IKZF3 (Aiolos), R137* and H195Y, discovered in a mouse model of pre-B-ALL. R137* IKZF3 mutation resulted in a truncated protein, while electrophoretic mobility shift assay showed that H195Y IKZF3 mutation resulted in a protein with altered DNA binding. 38B9 pre-B cell lines were generated expressing WT and H195Y IKZF3 proteins. Anti-IKZF3 ChIP-seq showed that H195Y IKZF3 interacted with a larger number of sites that were different than WT IKZF3. Treatment with interleukin-7 induced changes in gene expression in 38B9 cells expressing WT IKZF3, but did not induce any changes in gene expression in cells expressing H195Y IKZF3. Anti-STAT5 ChIP-seq showed that expression of H195Y IKZF3 resulted in redistribution of STAT5 binding sites in the genome. H195Y IKZF3 binding sites overlapped with a subset of STAT5 binding sites, including in the promoter of the Cish gene. These findings suggest that H195Y mutation of IKZF3 results in altered DNA binding specificity and altered binding of STAT5 to target genes.

Case Report: Prolonged remission of metastatic cisplatin-refractory nasopharyngeal carcinoma with Pembrolizumab.

Background: Epstein-Barr virus (EBV)-related nasopharyngeal cancer (NPC) is a common type of cancer in certain areas of the world such as southeast Asia, but is uncommon in Canada. There is currently no reliably effective standard treatment for incurable metastatic EBV-related NPC that progresses after first-line therapy with gemcitabine/cisplatin. Methods: With his consent, the health records of a patient with relapsed metastatic EBV-related NPC treated with pembrolizumab immunotherapy were retrospectively reviewed and reported. Case report: A male patient presented at age 15 with stage IVA EBV-related NPC. Despite response to initial chemoradiation and adjuvant chemotherapy, the patient experienced metastatic cancer relapse in lymph nodes and bone. There was initial response to gemcitabine/cisplatin chemotherapy, but the cancer progressed after 7 cycles. The patient was then switched to pembrolizumab and had a near complete clinical response after 14 cycles. Serum EBV titers have normalized and CT imaging shows only some healed bone metastasis. Retrospective assessment of tumor CPS PD-L1 was >20. Hypothyroidism developed, possibly due to radiation treatment, but otherwise he did not experience any other immune-mediated toxicities on or following treatment, which lasted in total 2 years with 41 cycles. To date, the patient has been observed off pembrolizumab for over one year and is highly functional without evidence of disease progression. Conclusion: This case illustrates the potential benefit of immunotherapy for improving survival and quality of life in selected patients with metastatic EBV-positive cisplatin-refractory NPC.

The E26 Transformation-Specific Family Transcription Factor Spi-C Is Dynamically Regulated by External Signals in B Cells.

Spi-C is an E26 transformation-specific transcription factor closely related to PU.1 and Spi-B. Spi-C has lineage-instructive functions important in B cell development, Ab-generating responses, and red pulp macrophage generation. This research examined the regulation of Spi-C expression in mouse B cells. To determine the mechanism of Spic regulation, we identified the Spic promoter and upstream regulatory elements. The Spic promoter had unidirectional activity that was reduced by mutation of an NF-κB binding site. Reverse transcription-quantitative PCR analysis revealed that Spic expression was reduced in B cells following treatment with cytokines BAFF + IL-4 + IL-5, anti-IgM Ab, or LPS. Cytochalasin treatment partially prevented downregulation of Spic. Unstimulated B cells upregulated Spic on culture. Spic was repressed by an upstream regulatory region interacting with the heme-binding regulator Bach2. Taken together, these data indicate that Spi-C is dynamically regulated by external signals in B cells and provide insight into the mechanism of regulation.

Circular RNA in colorectal cancer.

Circular RNA (circRNA) is a highly abundant type of single-stranded non-coding RNA. Novel research has discovered many roles of circRNA in colorectal cancer (CRC) including proliferation, metastasis and apoptosis. Furthermore, circRNAs also play a role in the development of drug resistance and have unique associations with tumour size, staging and overall survival in CRC that lend circRNAs the potential to serve as diagnostic and prognostic biomarkers. Among cancers worldwide, CRC ranks second in mortality and third in incidence. In order to have a better understanding of the influence of circRNA on CRC development and progression, this review summarizes the role of specific circRNAs in CRC and evaluates their potential value as therapeutic targets and biomarkers for CRC. We aim to provide insight in the development of therapy and clinical decision-making.