Abstract 1397: A novel ligand-independent Flt3 allele drives RANKL expression in a murine model of B-precursor acute lymphoblastic leukemia with CNS dissemination
Bibliographic record
Abstract
Abstract Survival rates for pediatric acute lymphoblastic leukemia (ALL) have improved dramatically, but outcomes for the 15% who relapse and for adults with ALL remain poor. Up to 40% of pediatric ALL patients require central nervous system (CNS) prophylaxis treatments that pose significant risk. We previously showed that p53−/− Rag-2−/− Prkdcscid;scid triple mutant (TM) mice spontaneously develop early B-cell ALL that disseminates to the CNS. We used this model to investigate molecular mechanisms that drive CNS dissemination of leukemic B-cells. Array comparative genomic hybridization revealed that TM ALLs have recurrent polyploidy or partial gains of telomeric chromosome 5 containing the Fms-like tyrosine kinase 3 (Flt3) locus. FLT3 is a type III receptor tyrosine kinase normally expressed on multi-potent hematopoietic progenitors. Small molecule FLT3 inhibitors abrogated proliferation of leukemic TM blasts in vitro, suggesting that Flt3 is a leukemic driver. During normal B-cell development, Flt3 is repressed by the PAX5 transcription factor, which also induces expression of B-lineage genes. Although TM ALLs expressed many genes indicative of B-lineage commitment, they ectopically over-expressed a truncated form of Flt3 (trFlt3) driven by an endogenous retrovirus long terminal repeat. The trFlt3 allele lacked most of the extracellular ligand-binding domain, but retained the trans-membrane region. Retroviral transduction of trFlt3 into BaF3 hematopoietic progenitor cells rendered their growth independent of interleukin-3. Phospho-flow cytometric profiling studies demonstrated that the signaling properties of trFLT3 are similar to those of FLT3-ITD, but are distinct from ligand-dependent FLT3 signaling. Thus, genomic rearrangements make Flt3 resistant to PAX5 repression and allow ectopic ligand-independent FLT3 signaling in TM B-ALL. Gene set enrichment analysis was used to identify genes downstream of Flt3 as potential drivers of B-ALL CNS dissemination. TM B-ALL blasts (but not murine B-ALL blasts lacking Flt3 expression) expressed RANKL, a key regulator of osteoclast differentiation and normal B-cell development. Cell surface expression of RANKL was absolutely correlated with the presence of trFLT3 protein, and RANKL cell surface expression was down-regulated by FLT3 inhibitors, suggesting that RANKL expression was controlled by trFLT3 signaling. We also found that interleukin-7, an important cytokine in B-cell development, up-regulates RANKL in normal pro-B cells. We are currently investigating if a RANKL antagonist can inhibit CNS dissemination of TM B-ALL expressing RANKL. Our studies have identified a novel Flt3 mutant allele with unusual signaling properties as a leukemic driver of early B-ALL, and provide a model for in vivo testing of the role of RANKL in mediating CNS dissemination of leukemic B-cell progenitors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1397. doi:1538-7445.AM2012-1397
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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 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.005 | 0.002 |
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".