Formation of dense filaments induced by runaway supermassive black holes

A narrow linear object extending $\sim 60$kpc from the centre of a galaxy at redshift $z \sim 1$ has been recently discovered and interpreted as a shocked gas filament forming stars. The host galaxy presents an irregular morphology, implying recent merger events. Supposing that each of the progenitor galaxies has a central supermassive black hole (SMBH) and the SMBHs are accumulated at the centre of the merger remnant, a fraction of them can be ejected from the galaxy with a high velocity due to interactions between SMBHs. When such a runaway SMBH (RSMBH) passes through the circumgalactic medium (CGM), converging flows are induced along the RSMBH path, and star formation could be ignited eventually. We find that the CGM temperature prior to the RSMBH perturbation should be below the peak temperature in the cooling function to trigger filament formation. While the gas is heated up temporarily due to compression, the cooling efficiency increases, and gas accumulation becomes allowed along the path. When the CGM density is sufficiently high, the gas can cool down and develop a dense filament by $z = 1$. The mass and velocity of the RSMBH determine the scale of the filament formation. Hydrodynamical simulations validate the analytical expectations. Therefore, we conclude that the perturbation by RSMBHs is a viable channel for forming the observed linear object. We also expect the CGM around the linear object to be warm ($T < 2 \times 10^5$ K) and dense ($n > 2 \times 10^{-5} (T/2 \times 10^5 \, K)^{-1} \, {\rm cm^{-3}}$).Comment: 10 pages, 10 figures, 1 table, submitted to MNRA

Imbalanced expression of polycistronic miRNA in acute myeloid leukemia

miR-1 and miR-133 are clustered on the same chromosomal loci and are transcribed together as a single transcript that is positively regulated by ecotropic virus integration site-1 (EVI1). Previously, we described how miR-133 has anti-tumorigenic potential through repression of EVI1 expression. It has also been reported that miR-1 is oncogenic in the case of acute myeloid leukemia (AML). Here, we show that expression of miR-1 and miR-133, which have distinct functions, is differentially regulated between AML cell lines. Interestingly, the expression of miR-1 and EVI1, which binds to the promoter of the miR-1/miR-133 cluster, is correlative. The expression levels of TDP-43, an RNA-binding protein that has been reported to increase the expression, but inhibits the activity, of miR-1, were not correlated with expression levels of miR-1 in AML cells. Taken together, our observations raise the possibility that the balance of polycistronic miRNAs is regulated post-transcriptionally in a hierarchical manner possibly involving EVI1,suggesting that the deregulation of this balance may play some role in AML cells with high EVI1 expression

Targeting CAM-DR and Mitochondrial Transfer for the Treatment of Multiple Myeloma

The prognosis of patients with multiple myeloma (MM) has improved dramatically with the introduction of new therapeutic drugs, but the disease eventually becomes drug-resistant, following an intractable and incurable course. A myeloma niche (MM niche) develops in the bone marrow microenvironment and plays an important role in the drug resistance mechanism of MM. In particular, adhesion between MM cells and bone marrow stromal cells mediated by adhesion molecules induces cell adhesion-mediated drug resistance (CAM-DR). Analyses of the role of mitochondria in cancer cells, including MM cells, has revealed that the mechanism leading to drug resistance involves exchange of mitochondria between cells (mitochondrial transfer) via tunneling nanotubes (TNTs) within the MM niche. Here, we describe the discovery of these drug resistance mechanisms and the identification of promising therapeutic agents primarily targeting CAM-DR, mitochondrial transfer, and TNTs

Refractory acute promyelocytic leukemia successfully treated with combination therapy of arsenic trioxide and tamibarotene: A case report

A 40-year-old male developed refractory acute promyelocytic leukemia (APL) after various treatments including all-trans retinoic acid, tamibarotene, arsenic trioxide (As2O3), conventional chemotherapy, and autologous peripheral blood stem cell transplantation. We attempted to use both tamibarotene and As2O3 as a combination therapy, and he achieved molecular complete remission. Grade 2 prolongation of the QTc interval on the electrocardiogram was observed during the therapy. The combination therapy of As2O3 and tamibarotene may be effective and tolerable for treating refractory APL cases who have no treatment options, even when they have previously been treated with tamibarotene and As2O3 as a single agent

Identification of disease-related aberrantly spliced transcripts in myeloma and strategies to target these alterations by RNA-based therapeutics

Abstract Novel drug discoveries have shifted the treatment paradigms of most hematological malignancies, including multiple myeloma (MM). However, this plasma cell malignancy remains incurable, and novel therapies are therefore urgently needed. Whole-genome transcriptome analyses in a large cohort of MM patients demonstrated that alterations in pre-mRNA splicing (AS) are frequent in MM. This manuscript describes approaches to identify disease-specific alterations in MM and proposes RNA-based therapeutic strategies to eradicate such alterations. As a “proof of concept”, we examined the causes of aberrant HMMR (Hyaluronan-mediated motility receptor) splicing in MM. We identified clusters of single nucleotide variations (SNVs) in the HMMR transcript where the altered splicing took place. Using bioinformatics tools, we predicted SNVs and splicing factors that potentially contribute to aberrant HMMR splicing. Based on bioinformatic analyses and validation studies, we provided the rationale for RNA-based therapeutic strategies to selectively inhibit altered HMMR splicing in MM. Since splicing is a hallmark of many cancers, strategies described herein for target identification and the design of RNA-based therapeutics that inhibit gene splicing can be applied not only to other genes in MM but also more broadly to other hematological malignancies and solid tumors as well

Epigenetic regulation of CD38/CD48 by KDM6A mediates NK cell response in multiple myeloma

Abstract Anti-CD38 monoclonal antibodies like Daratumumab (Dara) are effective in multiple myeloma (MM); however, drug resistance ultimately occurs and the mechanisms behind this are poorly understood. Here, we identify, via two in vitro genome-wide CRISPR screens probing Daratumumab resistance, KDM6A as an important regulator of sensitivity to Daratumumab-mediated antibody-dependent cellular cytotoxicity (ADCC). Loss of KDM6A leads to increased levels of H3K27me3 on the promoter of CD38, resulting in a marked downregulation in CD38 expression, which may cause resistance to Daratumumab-mediated ADCC. Re-introducing CD38 does not reverse Daratumumab-mediated ADCC fully, which suggests that additional KDM6A targets, including CD48 which is also downregulated upon KDM6A loss, contribute to Daratumumab-mediated ADCC. Inhibition of H3K27me3 with an EZH2 inhibitor resulted in CD38 and CD48 upregulation and restored sensitivity to Daratumumab. These findings suggest KDM6A loss as a mechanism of Daratumumab resistance and lay down the proof of principle for the therapeutic application of EZH2 inhibitors, one of which is already FDA-approved, in improving MM responsiveness to Daratumumab