BRD9 determines the cell fate of hematopoietic stem cells by regulating chromatin state.

ATP-dependent chromatin remodeling SWI/SNF complexes exist in three subcomplexes: canonical BAF (cBAF), polybromo BAF (PBAF), and a newly described non-canonical BAF (ncBAF). While cBAF and PBAF regulate fates of multiple cell types, roles for ncBAF in hematopoietic stem cells (HSCs) have not been investigated. Motivated by recent discovery of disrupted expression of BRD9, an essential component of ncBAF, in multiple cancers, including clonal hematopoietic disorders, we evaluate here the role of BRD9 in normal and malignant HSCs. BRD9 loss enhances chromatin accessibility, promoting myeloid lineage skewing while impairing B cell development. BRD9 significantly colocalizes with CTCF, whose chromatin recruitment is augmented by BRD9 loss, leading to altered chromatin state and expression of myeloid-related genes within intact topologically associating domains. These data uncover ncBAF as critical for cell fate specification in HSCs via three-dimensional regulation of gene expression and illuminate roles for ncBAF in normal and malignant hematopoiesis.

Aberrant EVI1 splicing contributes to EVI1-rearranged leukemia.

Detailed genomic and epigenomic analyses of MECOM (the MDS1 and EVI1 complex locus) have revealed that inversion or translocation of chromosome 3 drives inv(3)/t(3;3) myeloid leukemias via structural rearrangement of an enhancer that upregulates transcription of EVI1. Here, we identify a novel, previously unannotated oncogenic RNA-splicing derived isoform of EVI1 that is frequently present in inv(3)/t(3;3) acute myeloid leukemia (AML) and directly contributes to leukemic transformation. This EVI1 isoform is generated by oncogenic mutations in the core RNA splicing factor SF3B1, which is mutated in >30% of inv(3)/t(3;3) myeloid neoplasm patients and thereby represents the single most commonly cooccurring genomic alteration in inv(3)/t(3;3) patients. SF3B1 mutations are statistically uniquely enriched in inv(3)/t(3;3) myeloid neoplasm patients and patient-derived cell lines compared with other forms of AML and promote mis-splicing of EVI1 generating an in-frame insertion of 6 amino acids at the 3' end of the second zinc finger domain of EVI1. Expression of this EVI1 splice variant enhanced the self-renewal of hematopoietic stem cells, and introduction of mutant SF3B1 in mice bearing the humanized inv(3)(q21q26) allele resulted in generation of this novel EVI1 isoform in mice and hastened leukemogenesis in vivo. The mutant SF3B1 spliceosome depends upon an exonic splicing enhancer within EVI1 exon 13 to promote usage of a cryptic branch point and aberrant 3' splice site within intron 12 resulting in the generation of this isoform. These data provide a mechanistic basis for the frequent cooccurrence of SF3B1 mutations as well as new insights into the pathogenesis of myeloid leukemias harboring inv(3)/t(3;3).

The mechanism of treatment of multiple myeloma with metformin by way of metabolism.

INTRODUCTION: Multiple myeloma (MM) is a malignant hematologic tumor. Although many new drugs are currently found to significantly improve the median survival, MM is still not curable due partly to drug resistance recurrence. Epidemiological studies have shown that patients with type 2 diabetes have a high risk of malignancy, and patients' treatment with metformin could reduce the risk of cancer as well as associated mortality. MATERIAL AND METHODS: We used chemotherapeutics - melphalan combined with metformin or the single drug - to treat RPMI8226 cells and used a series of tests to detect the drug sensitivity, apoptotic rate, DNA damage and the concentration of ATP. SPSS 17.0 was used to analyze the data. RESULTS: The inhibitory effect of melphalan on RPMI8226 cells was significantly increased after metformin was added (p < 0.05), and the inhibitory effect was enhanced with the increasing concentration of melphalan. The comet assay showed that metformin increased melphalan-induced DNA damage and increased the apoptotic rate from 12.7 ±2.8% to 18.8 ±1.5% (p < 0.05). In the ATP concentration test, the concentration of ATP in the tumor cells was significantly decreased from 0.42 ±0.01 µmol/l to 0.08 ±0.02 µmol/l (p < 0.05). CONCLUSIONS: Metformin can promote DNA damage induced by melphalan and decrease the concentration of ATP in the process of repairing DNA damage to hinder the anti-apoptotic process of tumor cells, which showed the pesticide effect of the enhanced sensitivity of multiple myeloma cells to melphalan.

[Understanding and therapeutic targeting of aberrant mRNA splicing mechanisms in oncogenesis].

Splicing factor 3b subunit 1 (SF3B1) is the most commonly mutated RNA splicing factor identified in myelodysplastic syndrome (MDS), chronic lymphocytic leukemia, and uveal melanoma. The mechanisms by which SF3B1 mutations promote malignancy are poorly understood. Here, we integrated pan-cancer RNA sequencing to identify mutant SF3B1-dependent aberrant splicing events with a positive CRISPR screen to prioritize alterations that functionally promote oncogenesis. Our results indicated that diverse, recurrent SF3B1 mutations converge on the repression of bromodomain containing 9 (BRD9), a core component of the recently described non-canonical barrier-to-autointegration factor complex (ncBAF). Mutant SF3B1 recognizes intronic sequences within BRD9 as exons, thereby permitting inclusion of aberrant sequence (i.e., poison exon) that will result in the degradation of BRD9 mRNA. BRD9 depletion results in significant loss of ncBAF at CCCTC-binding factor (CTCF)-binding loci but has no impact on the localization of canonical BAF. These actions resulted in disturbed myeloid/erythroid differentiation and promoted the development of MDS and melanoma. Of note, correcting BRD9 mis-splicing in SF3B1-mutant cells with antisense oligonucleotides (ASOs), by targeting the poison exon with CRISPR-directed mutagenesis, or via the use of spliceosomal inhibitors are all potential therapeutic options. Our results implicate disruption of ncBAF as a critical factor promoting the development of the diverse array of cancers that carry SF3B1 mutations and suggest a mechanism-based therapeutic approach for treating these malignancies.

Might definitive local therapy of the primary tumor improve the survival benefits of metastatic prostate cancer?-evidence from a meta-analysis.

BACKGROUND: With the successful application of local therapy (LT) of the primary tumor in other metastatic disease and the demonstration of their better survival benefits, the traditionally seldom involved role of LT for metastatic prostate cancer (mPCa) had gained a lot of interest. Hence, this meta-analysis was conducted to clarify its efficacy in mPCa. METHODS: A comprehensive search of major databases (PubMed, EMBASE and Web of Science) was conducted for eligible studies, up to May 2019. The pooled hazard ratio (HR) with 95% confidence interval (CI) was utilized to evaluate the efficacy of LT for mPCa. RESULTS: A total of 12 eligible studies with 78,864 participants, containing 28 different comparisons were ultimately enrolled in this article. Our results showed that LT involving radical prostatectomy (RP) or radiation therapy (RT) for mPCa was related to enhanced overall survival (OS) (pooled HR =0.53, 95% CI: 0.47 to 0.61, I2=59.7%, P=0.015), decreased cancer-specific mortality (CSM) (pooled HR =0.42, 95% CI: 0.34 to 0.51, I2=63.1%, P=0.004) and lower all-cause mortality (ACM) (pooled HR =0.37, 95% CI: 0.31 to 0.45, I2=49.4%, P=0.115), compared with no local therapy (NLT). In subsequent stratified analysis, RP or RT was respectively linked to longer OS (pooled HR =0.49, 95% CI: 0.44 to 0.54, I2=0.0%, P=0.741; pooled HR =0.64, 95% CI: 0.56 to 0.72, I2=15.4%, P=0.306), lower CSM (pooled HR =0.37, 95% CI: 0.29 to 0.46, I2=35.2%, P=0.187; pooled HR =0.51, 95% CI: 0.42 to 0.63, I2=27.0%, P=0.250) and decreased ACM (pooled HR =0.31, 95% CI: 0.23 to 0.40, I2=56.4%, P=0.130; pooled HR =0.44, 95% CI: 0.34 to 0.56, I2=0.0%, P=0.856), compared with NLT. In terms of RP vs. RT, RP was linked to a decreased CSM (pooled HR =0.59, 95% CI: 0.53 to 0.66, I2=0.0%, P=0.653). CONCLUSIONS: In summary, our results shed light on the positive role of LT (RP or RT) for mPCa and meanwhile its feasibility and survival benefits had been demonstrated. Moreover, when compared with RT, RP showed its superiority in CSM. Upcoming prospective randomized controlled trials should be taken to validate our findings.