Evaluating splicing modulators for therapeutic impact in cohesin-mutant myeloid malignancies

• Applicant: Dr. Johann-Christoph Jann
• Subject Area: Hematology, Oncology
• Term: from 2020 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 450509131

Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML) are clonal diseases of mutated hematopoietic stem and progenitor cells characterized by abnormal differentiation and proliferative states, and associated with mutations and rearrangements affecting transcription factors, epigenetic regulators, chromatin modifiers and splicing genes. The core components of the cohesin complex STAG2, SMC1, SMC3, RAD21, as well as its modulators PDS5 and NIPBL are collectively mutated in 13% of patients with de novo AML, 21% of patients with secondary AML, and 11% of patients with MDS where they are associated with poor overall survival. Mutations in the cohesin genes are nearly always mutually exclusive, heterozygous, predicted loss-of-function mutations, which are thought to be acquired early during the progression from clonal hematopoiesis to MDS. Previous work discovered that cohesin mutations common in myeloid malignancies disrupt RNA splicing and render cells highly sensitive to broad-spectrum splicing inhibitors. We propose to use state-of-the-art approaches to characterize nascent transcription, RNA processing and RNA-protein interaction assays to define the aberrant RNA species that mediate this vulnerability and explore sensitivity of primary cohesin-mutant patient samples to splicing modulation. We hypothesize that cohesin complex mutations lead to altered RNA biogenesis and splicing and can serve as a therapeutic vulnerability in patients with cohesin-mutant MDS and AML.We propose the following specific Aims:1: Characterize the effect of cohesin mutations on RNA biogenesis in primary patient samples2: Determine the effect of cohesin mutations on sensitivity of primary AML cells to splicing modulation H3B-8800 und E71073: Characterize the nature of the interaction between the cohesin complex and SF3B complex using eCLIP-SeqWe expect to leverage extensive data from unbiased proteomic studies, genome-scale functional genetic screens, and drug sensitivity assays to identify new therapeutic approaches for patients with cohesin mutant cancers and to discover novel mechanisms of transformation by these genetic drivers. The findings fromthese studies have the potential to lead directly to one or more clinical trials within the next several years.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professorin Zuzana Tothova, Ph.D.