Abstract BS01-1: Genetic and non-genetic mechanisms contribute to longterm clonal growth dynamics and therapy resistance
Bibliographic record
Abstract
Abstract The cellular and molecular basis for intra-tumoral heterogeneity is poorly understood. Tumor cells can be genetically diverse due to mutations and clonal evolution resulting in intra-tumoral functional heterogeneity. Often proposed as mutually exclusive, cancer stem cell (CSC) models postulate that tumors are cellular hierarchies sustained by CSC heterogeneity due to epigenetic differences (i.e. long term tumor propagation only derives from CSC). Two lines of evidence support the CSC model in leukemia. We have recently developed gene signatures specific to either AML LSC or normal HSC and found they share a set of genes that define a common stemness program. Only these stem cell related gene signatures were significant independent predictors of patient survival in large clinical databases. Thus, determinants of stemness influence clinical outcome of AML across a spectrum of mutations indicating that many genetic abnormalities coalesce around stem cell properties. Second, we have carried out a series of combined genetic and functional studies of the LSC from either B-ALL or AML that point to commonalities between clonal evolution and CSC models of cancer. LSC from diagnostic patient samples were genetically diverse and reconstruction of their genetic ancestry showed that multiple LSC subclones were related through a complex branching evolutionary process. The discovery that specific genetic events influence L-IC frequency and that genetically distinct L-IC evolve through a complex evolutionary process indicates that genetic and functional heterogeneity are highly inter-related. Finally, we have also begun to study paired diagnostic (Dx) and relapse (Rx) samples and found that rare Dx subclones are chemotherapy resistant and become enriched at Rx. Collectively, our study points to the need to develop therapies that effective target all genetic subclones present in a tumor and also ensure that cells possessing stemness properties are eliminated to prevent further evolution and recurrence. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr BS01-1.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.006 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".