Bone Marrow Histopathological Changes in Neoplastic and Non-Neoplastic Diseases

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Abstract

In FY23, in collaboration with Dr. Kazandjian and Dr. Young, we participated in a study investigating oncogenic RAS mutations in multiple myeloma (MM). Multiple myeloma is the second most common hematological malignancy, accounting for nearly 35,000 new cancer cases a year within the United States. Substantial progress has been made treating this disease with the introduction of proteasome inhibitors and immunomodulatory drugs (IMiDs). However, MM remains incurable and most patients will relapse and become refractory to existing treatments. Mutations targeting the RAS pathway are common in MM and associated with resistance to these therapies. KRAS and NRAS are each mutated in about 20% of newly diagnosed MM cases. MM is unusual in this regard, as other RAS-dependent tumor types typically rely on a single isoform of RAS. RAS can signal through multiple effector pathways, perhaps most characteristically by activation of the classical MAP kinase (MAPK) pathway through RAF, MEK and ERK. Despite the high frequency of RAS mutations, the majority of MM tumors harboring RAS mutations have no detectable MEK activity, and MEK inhibitors have only had modest success treating MM patients. These findings suggest that RAS-dependent activation of the classical MAPK pathway is not the sole mode of RAS signaling in malignant plasma cells and point to an unidentified role for oncogenic RAS signaling in this disease. The mechanisms of pathogenic RAS signaling in this disease remain enigmatic and difficult to inhibit therapeutically. This study revealed that oncogenic RAS commandeers amino acid sensing machinery to aberrantly activate mTORC1 in MM patients. An unbiased proteogenomic approach to dissect RAS signaling in MM discovered that mutant isoforms of RAS organize a signaling complex with the amino acid transporter, SLC3A2, and MTOR on endolysosomes, which directly activates mTORC1 by co-opting amino acid sensing pathways. Investigation of MM tumors with high expression of mTORC1-dependent genes showed them to be more aggressive and enriched in RAS mutations. The MTOR-RAS PLA to detect MTOR and RAS interactions in formalin-fixed paraffin-embedded (FFPE) bone marrow biopsies from a cohort of 28 MM patients with known RAS mutation statuses showed that 33% of MM cases with KRAS or NRAS mutations (5/15; 3 KRAS, 2 NRAS) had strong MTOR-RAS PLA signals. The results revealed interactions between RAS and MTOR in MM patient tumors harboring mutant RAS isoforms. Further experiments showed inhibition of RAS-dependent mTORC1 activity synergized with MEK and ERK inhibitors to quench pathogenic RAS signaling in MM cells. This study redefined the RAS pathway in MM and provided a mechanistic basis to target this mode of RAS signaling.