A5018096320- Multiple Myeloma Research and Treatments
- CAR-T cell therapy research
- Immune Cell Function and Interaction
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Acute Myeloid Leukemia Research
- Protein Degradation and Inhibitors
- Quinazolinone synthesis and applications
- Sarcoma Diagnosis and Treatment
- Histone Deacetylase Inhibitors Research
- Ubiquitin and proteasome pathways
- Synthesis and Biological Evaluation
- Cancer Genomics and Diagnostics
- Peptidase Inhibition and Analysis
- Monoclonal and Polyclonal Antibodies Research
- Chemokine receptors and signaling
University of Colorado Anschutz Medical Campus
2019-2024
University of Colorado Denver
2019
University of Colorado Cancer Center
2019
<p>HIF1 Signaling Pathway Genes Overexpressed in IGH-MM.</p>
<p>Relapse and disease progression associated with dysregulated apoptosis increasing drug resistance. <b>A,</b> Volcano plot showing the differential gene expression between LCE-multiple myeloma (MM) cells at timepoint 1 (diagnosis) LCE-MM 2 (first relapse, 1,042 genes higher in diagnosis, 281 first indicated by green dots for l<sub>2</sub>FC > 0.25, <i>P</i> < 0.05). Tested linear regression, <i>n</i> = 4,370 relapse....
<p>Top 15 genes higher in LCE-MM vs IGH-MM at diagnosis.</p>
<p>Gene Expression at First Relapse Exhibiting a Dysregulation of Apoptosis.</p>
<p>Immunoglobulin Heavy Chain Genes were the Top Overexpressed in IGH-MM.</p>
<div>Abstract<p>High-risk multiple myeloma is genomically unstable, comprising heterogeneous populations of tumor cells that evolve over time. Light chain escape (LCE) a clinical phenomenon observed when light chains rise separately from M-spike values, which implies divergent evolution. We sought to understand LCE by performing high-depth transcriptomic and phenotypic studies. performed single-cell RNA-sequencing (scRNA-seq) <i>ex vivo</i> drug sensitivity profiling...
<p>Oxidative Phosphorylation Pathway Genes Overexpressed in LCE-MM.</p>
<p>Patient with two multiple myeloma (MM) subpopulations correlating separately to monoclonal protein and free light chain detection through the course of disease. <b>A,</b> UMAP clustering analysis bone marrow biopsy samples from patient #1093 at all three timepoints showed distinct MM cells (LCE-MM IGH-MM), along expected normal cell types. <b>B,</b> Both displayed transcript expression for prototypical markers including high <i>CD138</i>,...
<p>Top 15 genes higher in IGH-MM vs LCE-MM at diagnosis.</p>
<p>Infer Copy Number Variant Analysis for Subclonal Tracking.</p>
<p>Characterization of LAMP5 Effects on MM cell Prognosis, Prognosis and Viability.</p>
<p>Normal Bone Marrow Cell Populations Across Timepoints.</p>
<p>Multiple myeloma (MM) subpopulation gene-set exhibits osteolytic features and is detrimental to OS. <b>A,</b> Through the disease course for patient #1093, spikes in serum calcium occurred during periods of activity with high levels LCE-MM. <b>B,</b> The GEP70 score high-risk MM was significantly higher LCE-MM compared IGH-MM subpopulation. <b>C,</b> Five key genes were even more upregulated IGH-MM. <b>D,</b> In MMRF cohort, 325...
<p>The IGH-MM Gene Signature Was Not Associated with Adverse Prognosis.</p>
<p>Patients from the CoMMpass database with LCE have a poor prognosis. <b>A,</b> Fifteen patients identified showed significantly shorter PFS diagnosis than those without LCE. <b>B,</b> Patients OS <b>C,</b> high <i>LAMP5</i> expression had trend toward compared and low <i>LAMP5</i>. <b>D,</b> nonsignificantly <b>E,</b> time to diffuse lytic lesions <b>F,</b> In particular, all both at...
<p>Differential myeloma drug sensitivity profiles of malignant subpopulations at diagnosis. <b>A,</b> Flow cytometry showed a monotypic population by typical markers CD138 and CD38 (left), but rarer with CD45 expression, or without CD19 (right) that were not detected scRNA-seq. <b>B,</b> Of the cell surface proteins measured flow cytometry, mRNA for CD46 most differential expression (l<sub>2</sub>FC = 0.44, <i>P</i> 5.76 ×...
<p>Clinical Characteristics of Patient #1093</p>
<p>Differential gene expression between multiple myeloma (MM) subpopulations at diagnosis. <b>A,</b> Volcano plot showing genes expressed higher levels timepoint 1 in LCE-MM and those IGH-MM with log<sub>2</sub> fold-change (l<sub>2</sub>FC) cutoff above 0.25 (vertical dashed lines) statistical significance defined as comparison adjusted <i>P</i> value < 0.05 (horizontal line) by linear regression (LCE-MM <i>n</i> = 4,370...
<p>The LCE-multiple myeloma (MM) subpopulation conferred a poor prognosis and represented genetic subclone of MM cells. <b>A,</b> FGFR3 expression distribution was high across all cells at diagnosis, but low or undetectable in normal cell populations, supporting clonal t(4;14) malignant <b>B</b> <b>C,</b> InferCNV analysis identified chromosome 1 gain 13 loss both subpopulations, consistent with findings by FISH. <b>D,</b> Alluvial plot...
<p>Patients Identified from the CoMMpass Dataset with Light Chain Escape.</p>
<p>Top 15 genes increased in diagnosis vs relapsed LCE-MM.</p>
<p>Analysis without IGH Genes Still Shows Two Subpopulations.</p>
Immunomodulatory drugs (IMiDs), such as lenalidomide and pomalidomide, are a cornerstone of multiple myeloma (MM) therapies, yet the disease inevitably becomes refractory. IMiDs exert cytotoxicity by inducing cereblon-dependent proteasomal degradation IKZF1 IKZF3, resulting in downregulation oncogenic transcription factors IRF4 MYC. To date, clinical IMiD resistance independent cereblon or IKZF1/3 has not been well explored. Here, we investigated roles MYC this context.