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.

Beth Israel Deaconess Medical Center Harvard Medical School Boston MA USA

Department of Hemato oncology University Hospital Ostrava Ostrava Czech Republic

Department of Hemato oncology University of Ostrava Ostrava Czech Republic

Department of Hematology and Oncology Tokai University School of Medicine Isehara Japan

Department of Medicine Department of Oncology University of Alberta Edmonton AB Canada

Department of Pathology Brigham and Women's Hospital Harvard Medical School Boston MA USA

Institute of Medical and Public Health Research School of Medicine Ilia State University Tbilisi Georgia

Jerome Lipper Multiple Myeloma Disease Center Dana Farber Cancer Institute Harvard Medical School Boston MA USA

Molecular Diagnostic Laboratory Dana Farber Cancer Institute Boston MA USA

Veterans Administration Boston Healthcare System West Roxbury MA USA

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