Abstract 5173: Genetic profiling of central nervous system dissemination of B-acute lymphoblastic leukemia reveals clonal selection and therapeutic vulnerability
Bibliographic record
Abstract
Abstract B-cell acute lymphoblastic leukemia (B-ALL) readily disseminates to the leptomeninges of the central nervous system (CNS). CNS involvement is more frequent in certain poor prognosis subgroups including patients with MLL-AF4 translocations, and late CNS relapse is often lethal. The biology and clonal history of CNS leukemia are poorly defined and consequently therapies exploiting drivers of metastasis are lacking. To characterize leptomeningeal leukemia we performed targeted DNA sequencing, SNP copy number analysis, RNA sequencing, and functional analysis on cells isolated from the bone marrow (BM) and CNS of xenografts generated from a cohort of paired diagnosis and relapse samples from 14 B-ALL patients. The majority of patient samples disseminated to the CNS following intrafemoral injection into irradiated NSG mice, with greater CNS involvement in xenografts derived from relapse patient samples. Secondary transplantation of both BM- and CNS-purified cells demonstrated their capacity to re-engraft BM, CNS, and spleen. Targeted-sequencing results were analyzed using a Bayesian clustering method to determine the clonal composition of matched BM and CNS, demonstrating discordance in subclonal prevalence in nearly half the xenografts tested. Xenografts derived from two patient samples demonstrated recurrent enrichment of a particular subclone in the CNS versus BM. Similarly, copy number analysis identified frequent discordance between BM and CNS tissues within individual mice. All xenografts from one patient exhibited chromosome 6p and 17p hemi-deletions that were exclusive to CNS cells. While these data suggest that individual B-ALLs harbor subclones with CNS tropism, there were no recurrently enriched single nucleotide mutations or copy number alterations across all patients. RNA-sequencing of 45 BM and CNS pairs from primary xenografts demonstrated that CNS-isolated cells were consistently distinct from their matched BM. GSEA analysis of xenografts generated from patients with MLL-AF4 translocations (MLL) (n=2 patients, 26 mice), identified CNS cell enrichment of gene sets related to mRNA translation and nascent peptide elongation compared to BM. MLL-CNS cells exhibited altered rates of protein synthesis compared to BM cells from the same mouse. The clinically-approved translation inhibitor omacetaxine mepesuccinate effectively diminished protein translation rates of CNS isolated cells and reduced CNS engraftment by four fold in xenografts derived from two MLL-AF4 patients. These data demonstrate that the CNS microenvironment selects for the outgrowth of B-ALL cells with genetically and/or biologically distinct properties. Moreover, we demonstrate that in MLL-AF4 patients, altered protein synthesis occurs in CNS dissemination and that targeting this process may clinically benefit patients with CNS disease. Citation Format: Robert J. Vanner, Stephanie M. Dobson, Ildiko Grandal, Olga Gan, Jessica McLeod, James Kennedy, Veroniqu Voisin, Abdellatif Daghrach, Erwin M. Schoof, Cynthia Guidos, Jayne Danska, Esme Waanders, Mark Minden, Charles G. Mullighan, John E. Dick. Genetic profiling of central nervous system dissemination of B-acute lymphoblastic leukemia reveals clonal selection and therapeutic vulnerability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5173.
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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 | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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".