Chromatin state of different gain region. The regions of gain tend to fall within active chromatin regions with G3, G4, G5, G6, and G8 lying exclusively within A-compartments (100%) across B-cell differentiation states and MM cell lines (U266, RPMI8226, and KMS11). The G1 region also followed this pattern with the exception of KMS11 (where A-compartment represented only 78% of the region). The G2 region showed variability between the normal and malignant phenotype, with moderate switching from to B-compartments of 24%, 21%, and 37% in U266, RPMI8226, and KMS11 respectively. The compartment profile of the G7 region is interesting as each sample contained considerable B-compartment percentage (range 16-82%) but within the conserved A-compartment across all samples lies the well characterised oncogene ABL2. The G9 region showed the greatest variability across all samples and was shifted more towards inactive chromatin (range 45-97%). NBC=Naïve B-cell, MBC=Memory B-cell, GCBC=Germinal Center B-cell, PC=plasma cell.
ARTICLE ABSTRACT
Chromosome 1 (chr1) copy-number abnormalities (CNA) and structural variants (SV) are frequent in newly diagnosed multiple myeloma (NDMM) and are associated with a heterogeneous impact on outcomes, the drivers of which are largely unknown.
A multiomic approach comprising CRISPR, gene mapping of CNAs and SVs, methylation, expression, and mutational analysis was used to document the extent of chr1 molecular variants and their impact on pathway utilization.
We identified two distinct groups of gain(1q): focal gains associated with limited gene-expression changes and a neutral prognosis, and whole-arm gains, which are associated with substantial gene-expression changes, complex genetics, and an adverse prognosis. CRISPR identified a number of dependencies on chr1 but only limited variants associated with acquired CNAs. We identified seven regions of deletion, nine of gain, three of chromothripsis (CT), and two of templated insertion (TI), which contain a number of potential drivers. An additional mechanism involving hypomethylation of genes at 1q may contribute to the aberrant gene expression of a number of genes. Expression changes associated with whole-arm gains were substantial and gene set enrichment analysis identified metabolic processes, apoptotic resistance, signaling via the MAPK pathway, and upregulation of transcription factors as being key drivers of the adverse prognosis associated with these variants.
Multiple layers of genetic complexity impact the phenotype associated with CNAs on chr1 to generate its associated clinical phenotype. Whole-arm gains of 1q are the critically important prognostic group that deregulate multiple pathways, which may offer therapeutic vulnerabilities.
