Targeting oncogenic mRNA-networks in multiple myeloma

• Applicants: Privatdozentin Dr. Annamaria Brioli; Professor Dr. Florian Heidel
• Subject Area: Hematology, Oncology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 530321626

Despite advances made in the last decades, multiple myeloma (MM) is still an incurable disease. The persistence of malignant clones following cytotoxic or targeted therapy is one of the major determinants of this dismal outcome. Therefore, strategies that specifically target resistant cells while leaving normal cells unaffected are highly needed. Recently our group has provided further evidence for the pleiotropic nature of cold shock protein YBX1 acting as a splicing factor in JAK2-mutated myeloproliferative neoplasms and – in contrast – stabilizing oncogenic transcripts in models of acute myeloid leukemia. In MM overexpression of YBX1 has been linked to disease progression and recent data suggests a functional role in disease development. However, the mechanisms by which YBX1 acts in MM are not sufficiently understood. Very recently, a first pharmacologic compound targeting YBX1 has been developed. Our preliminary data show that pharmacological and genetic inhibition of YBX1 impairs cell growth in MM cell lines, mainly by triggering apoptosis. Importantly, the most sensitive cell lines are those most resistant to conventional MM therapeutics, such as immuno-modulators (IMiDs) and proteasome inhibitors. This difference in sensitivity cannot be fully explained by global gene expression changes in sensitive versus resistant cell lines. The goal of this research proposal is to elucidate the precise function of the pleiotropic protein YBX1 in MM and to clarify the mechanistic aspects of pharmacologic YBX1 modulation. First, we will validate our preliminary data in primary patient samples, as well as in in vivo models. Using genome wide CRISPR/Cas9 editing and global proteomic analysis we will assess for the functional aspects of YBX1 inhibition. Moreover, we aim to confirm binding of relevant oncogenic mRNAs as mechanistic basis of pharmacologic YBX1 inhibition in MM. These data will enable us to identify functional dependencies on YBX1 function. These dependencies will be validated in vitro and in vivo, including in PDX models, to identify possible combinatorial treatments for translation into clinical use. Prospectively, destabilization of oncogenic mRNA networks through YBX1-inhibition represents a novel mechanism to target MM cells with resistance to established treatment modalities such as proteasome inhibitors and IMiDs.

• DFG Programme: Research Grants