Abstract: The disclosure provides artificial nucleic acid introns configured for selective splicing in cells with aberrant RNA splicing activity, e.g., neoplastic cells. The artificial intron can comprise a 5? splice site, a canonical 3? splice site, at least one cryptic 3? splice site, a pyrimidine-rich domain, and at least one branchpoint. Also provided are constructs integrating the artificial introns with exons in a configuration that, when the artificial intron is spliced out by the aberrant RNA splicing factors, encode a functional protein. Also disclosed are methods that employ the disclosed platform of selective expression, including, targeted gene therapy methods (e.g., in cancers), diagnostics and imaging, and drug screening.

Abstract: The disclosure provides methods of enhancing susceptibility of neoplastic, transformed, and/or cancer cells (“cancer cells”) to immunotherapeutic agents. The methods comprise contacting the cancer cell with an agent that modulates RNA splicing. In some embodiments, the method further comprise contacting the cancer cell with the immunotherapeutic agent, such as an immune checkpoint inhibitor. The disclosure also provides compositions and/or methods for treating a subject with cancer. In some embodiments, the disclosure provides compositions and methods for combination therapy that comprises administering to a subject with cancer an effective amount of an agent that modulates RNA splicing and a therapeutically effective amount of an immunotherapeutic agent, such as an immune checkpoint inhibitor.

Abstract: The current disclosure relates to methods and compositions for increasing functional expression of BRD9 in a cell. The methods and compositions can be incorporated into methods for treating cancer through the administration of BRD9 activating therapies. Accordingly, aspects of the disclosure relate to compositions and methods for treating cancer, a pre-malignant disease, or a dysplastic disease in a subject. The method can comprise administering a BRD9 activating therapy to the subject.

Abstract: In the present invention, inventors have used high throughput sequencing to identify novel mutations in ABCA1 in CM ML patient samples. Further studies in a mouse model of myelomonocytic leukemia driven by hematopoietic Tet2 deficiency have shown that these somatic mutations abrogate the tumor suppressor function of WT ABCA1, resulting in the failure to suppress canonical IL3-receptor beta signaling-driven myelopoiesis. The loss of the myelo-suppressive function of ABCA1 mutants can be overcome by raising HDL levels through overexpression of the human apolipoprotein A-1 (apoA-1) transgene. Inventors have also shown that both IL-3Rbeta blocking antibody and cyclodextrin prevented the proliferation of ABCA1 mutant-transduced Tet2 deficient BM cells similar to the effect of ABCA1-WT overexpression.

Abstract: A method of preventing a hematopoietic disorder or malignancy in a high risk subject, the subject being positive for one or more mutation in a splicing factor, is disclosed. The method comprising administering to the subject an agent capable of inhibiting spliceosomal activity, with the proviso that said agent does not inhibit RBM39 activity.

Abstract: The presently disclosed subject matter relates to the use of one or more biomarkers to evaluate the likelihood that an EZH2 inhibitor would produce an anti-cancer effect in a subject. It is based, at least in part, on the discovery that loss of BAP1 results in the upregulation of EZH2 expression and activity. In a specific non-limiting embodiment, the method comprises obtaining a sample of the cancer from a subject, and determining, in the sample, the expression level of an BAP1 biomarker, where if the BAP1 biomarker is absent or expressed at lower level in the cancer as compared to a reference control level, then administering a therapeutically effective amount of an EZH2 inhibitor to produce an anti-cancer effect.

Abstract: Provided are methods of determining the amount of a BRAF V600E mutation over time in a subject with Langerhans Cell Histiocytosis (LCH) or Erdheim-Chester Disease (ECD) who is being treated with vemurafenib or dabrafenib.