Abstract A25: Evolving functional heterogeneity in B-acute lymphoblastic leukemia
Bibliographic record
Abstract
Abstract Despite high survival rates for children with acute lymphoblastic leukemia (ALL), only 40% of adult patients will achieve long-term disease-free survival, and relapses in both pediatric and adult ALL are often fatal. B-ALL leukemic blasts exhibit considerable subclonal genomic diversity. In 50% of patients, the clones present at relapse are not the dominant clone at diagnosis, but have evolved from a minor or ancestral clone. B-ALL subclonal diversity also exists in leukemia-initiating cells (L-IC) that are functionally capable of initiating xenografts. In order to investigate the clonal evolution during disease progression and link genetic diversity with functional characteristics, including differentiation, migratory properties, L-IC frequency and therapy resistance, we performed in depth genomic and functional analysis of 14 paired diagnosis/relapse samples from adult and pediatric B-ALL patients of varying cytogenetics. Time to relapse ranged from 6 to 97 months. Patient samples were subjected to whole exome/genome sequencing, SNP analysis and RNA sequencing. Diagnosis-specific, relapse-specific and shared variants at both clonal and subclonal frequencies were identified. Limiting dilution analysis by transplantation of CD19+ leukemic blasts into immune-deficient mice (xenografts) identified no significant trend in enrichment in L-IC frequency between paired patient samples with a median frequency of 1 in 2691. Despite similar frequencies of L-IC, functional differences within identically sourced patient xenografts were observed, including increased leukemic dissemination of relapse cells to the spleen and/or central nervous system, differences in engraftment levels and differences in immunophenotypes. Copy number analysis and ongoing variant sequencing of the xenografts, in comparison to the patient sample from which they were derived, has uncovered clonal variation and the outgrowth of ‘relapse-like’ subclones in xenografts transplanted with the diagnostic sample. Interrogation of the therapeutic response of these subclones in secondary xenografts displayed evidence of resistance to standard chemotherapeutic agents (vincristine and L-asparaginase). Therefore we have shown evidence that relapse subclones/ ancestral clones present at diagnosis possess functional advantages over other diagnostic clones. Overall, this work will provide further understanding of the heterogeneity identified in B-ALL and how it contributes to lymphoid leukemogenesis, therapy failure, and disease recurrence. Citation Format: Stephanie M. Dobson, Robert Vanner, Esmé Waanders, Jessica McLeod, Olga I. Gan, Zhaohui Gu, Debbie Payne-Turner, Xiaotu Ma, Yiping Fan, Pankaj Gupta, Michael Rusch, John Easton, Cynthia J. Guidos, Jayne S. Danska, Jinghui Zhang, Mark D. Minden, Charles G. Mullighan, John E. Dick. Evolving functional heterogeneity in B-acute lymphoblastic leukemia. [abstract]. In: Proceedings of the Fourth AACR International Conference on Frontiers in Basic Cancer Research; 2015 Oct 23-26; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2016;76(3 Suppl):Abstract nr A25.
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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 | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".