Role of Spleen Tyrosine Kinase Signaling in Early B Cell Acute Lymphoblastic Leukemia.
Bibliographic record
Abstract
Abstract Abstract 3092 Poster Board III-29 Introduction Early B cell acute lymphoblastic leukemia (B-ALL) is the most common type of childhood malignancy, characterized by abnormal accumulation and proliferation of progenitor-B or precursor-B (pre-B) cells. Current challenges associated with B-ALL treatment include fatal relapses, treatment-related toxicities and long-term morbidities underscoring a need to develop new targeted therapies aimed at eradicating leukemia cells and their stem cells. To achieve this, a better understanding of molecular mechanisms involved in leukemia initiation and progression is required. Our laboratory developed p53-/- PrkdcSCID/SCID double mutant (DM) strain as a mouse model of early B-ALL. We showed that DM leukemias progress through discrete developmental stages of leukemogenesis despite the absence of a pre-B cell receptor (pre-BCR), a crucial checkpoint in B cell development. Spleen tyrosine kinase (SYK), a key proximal component of pre-BCR signaling, was activated in the DM leukemias despite the absence of pre-BCR and was required for their survival. Approximately 70% of pediatric pre-B-ALLs also do not express pre-BCR, which lead us to investigate SYK signaling in human pre-B-ALL and to test potential therapeutic application of SYK inhibition in these leukemias. Patients and Methods We examined 22 viably frozen primary pediatric pre-B-ALL bone marrow samples to test their responses to SYK inhibition in vitro and in vivo and have investigated the molecular basis for aberrant SYK-mediated signaling in B-ALL. Results Western blot analyses revealed that SYK and BLNK, a dominant target of SYK, were expressed in pre-B-ALL patient samples. The majority of human pre-B ALL samples tested (14/22) displayed significantly attenuated proliferation in the presence of SYK inhibitors suggesting that SYK is necessary for their survival and/or proliferation. Treatment with SYK inhibitor R406 prevented phosphorylation of downstream SYK targets including BLNK and PLC-γ2. We are continuing to study the effects of SYK inhibition using phospho-flow cytometry and genome wide expression arrays. Preliminary data will also be presented on therapeutic efficacy of an orally bioavailable form of R406-mediated SYK inhibition in vivo by xenotransplantation of human leukemias into immuno-deficient mice. Conclusions Understanding the molecular mechanisms of pre-BCR-independent SYK activation involved in proliferation and survival of leukemic blasts may provide a rational basis for development of effective treatment for ALL. Specifically, targeted therapeutic inhibition of SYK signaling may be effective B-ALL treatment that may improve outcomes of current treatment regiments with minimal additional treatment-related toxicity. Disclosures Pine: Rigel Pharmaceuticals: Employment, Equity Ownership. Hitoshi:Rigel Pharmaceuticals: Employment, Equity Ownership.
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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) | 0.002 | 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".