Getting Ahead of Treatment Resistance in Multiple Myeloma
It has been increasingly appreciated that drug resistance can occur as a result of non-genetic cellular plasticity. Julia Frede, PhD and her research colleagues showed that individual myeloma cells have multiple distinct transcriptional states and that clinical agents promoted transcriptional reprogramming. They observed that treatment induced the expression of a distinct set of actionable immunotherapy targets, such as CXCR4, which can be exploited to keep treatment resistance at bay.
Highlighting the impact of their work, Dr. Frede says, “we show that it is possible to modulate immunotherapy target expression in multiple myeloma cells using existing therapies and therefore delineate a way to overcome the treatment resistance that develops almost invariably in this disease using combination therapies.”
In work reported in Nature Cell Biology, Dr. Frede and her colleagues performed single-cell RNA sequencing analyses of myeloma cells and CD45+ immune cells from the bone marrow or blood of eight patients and two healthy donors. The patients were being treated with elotuzumab, pomalidomide, bortezomib, and dexamethasone in a clinical trial. The authors found co-expression of unrelated gene expression signatures in the same cell. They also observed expression of genes that were not normally detectable in plasma cells and confirmed that the transcriptional states of myeloma cells diverged from normal plasma cells toward more immature progenitor populations of lymphoid or other hematopoietic precursors.
Dr. Frede and her colleagues found that while canonical plasma cell regulators remained active in myeloma cells, the transcription factors in myeloma cells had additional target genes that were not observed in the plasma cell transcriptional module. Analyzing single-cell ATAC sequencing data, they observed an increase in accessible peaks. Many of these accessible regions fell into heterochromatin, with a greater fraction of the peaks in intronic and intergenic regions, suggesting a gain in enhancers. They found that 129 out of the 429 rewired transcription factors in myeloma had differential motif accessibility. All these data suggest that derepression of heterochromatin in myeloma allows for binding of transcription factors and expression of genes not normally expressed in plasma cells.
Looking at cells collected from the patients after 4 cycles of treatment (collected on cycle 5 day 1), they found that treatment induced: a) increased overall regulon activity, b) significant changes in chromatin accessibility, and c) increased average number of enhancers per gene in myeloma cells. Among the top upregulated genes following treatment was the surface marker CXCR4. Increased accessibility in an enhancer peak associated with CXCR4 was observed, suggesting a change in epigenetic activation of CXCR4. They confirmed in in vitro studies that treatment with pomalidomide (P), bortezomib (V) and dexamethasone (D) induced CXCR4 expression, an effect that can primarily be attributed to dexamethasone. Leveraging this finding, they showed increased treatment efficacy when myeloma cells are first treated with PVD followed by a CXCR4 inhibitor.
Dr. Frede received an AACR-Amgen Fellowship in Clinical/Translational Cancer Research in 2019 as a postdoctoral fellow at the Dana Farber Cancer Institute. With support from the fellowship and mentorship by Jens G. Lohr, MD, PhD, she had set out to define therapeutic approaches that could overcome multiple myeloma therapy resistance by delineating targetable changes in myeloma functional states. This current Nature Cell Biology manuscript presents results that have been supported by her fellowship, at least in part.
Further highlighting the impact of the AACR grant on her research and career, she shares, “the 2019 AACR-Amgen Fellowship in Clinical/Translational Cancer Research has allowed me to pursue my research interests and has promoted my career development with the aim of launching a successful career as an independent researcher in the field of hematologic malignancies.”