Menin inhibitors as targeted therapeutics in KMT2a rearranged infant leukemia and the identification of effective treatment combinations.
Bibliographic record
Abstract
10024 Background: KMT2a rearrangements are a hallmark of infant (less than 1 year of age) leukemia and are associated with poor prognosis. Menin is a ubiquitous protein that binds to the N-terminal of the KMT2a-fusion protein to mediate the oncogenic activity of KMT2a-rearranged leukemia cells. In this study, we evaluated the effect of multiple menin inhibitors and effective drug combinations for the treatment of KMT2A-rearranged infant leukemia. Methods: FISH analysis and immunoblotting confirmed the presence of KMT2a-fusion in the primary patient samples and cell lines studied. Lymphocytes from healthy donors were used as controls. Cells were treated with various concentration of multiple menin inhibitors for 72 hours and growth inhibition was measured using alamar blue assay. Infant leukemia cells were treated with a panel of FDA-approved agents (n = 221) to identify potential synergy, additive- and antagonistic-effects with specific menin inhibitors. Therapeutic drug interaction properties were established by calculating combination indices (CI) using the Chou-Talalay method. Mode of cell death and cellular target modulations were determined by western blot analysis. The effect of targeting menin in the context of the leukemogenic bone marrow microenvironment was determined through stromal cell co-cultures. Results: A comprehensive analysis of menin inhibitors on infant leukemia cell lines and primary patient cells exhibited significant and quantitatively diverse responses in cells with distinct molecular properties. Within the panel of menin inhibitors, infant B-ALL cells were found to be more sensitive to MI-463, MI-503 and MI-136 with a mean IC50 of 5.9µM, 6.1µM and 10.2µM, respectively. On the other hand, MI-3 exhibited an IC50 of 35.6µM. The cytotoxic effect of menin inhibitors on normal lymphocytes was minimal, suggesting a favourable therapeutic window (p < 0.0001). High-throughput screening with a library of > 200 FDA-approved drugs revealed significant sensitivity of distinct infant leukemia cells to proteasome, HDAC and CDK9 inhibitors. Among these, substantial drug synergy was observed between menin and proteasome inhibitors. For example, carfilzomib synergised with menin inhibitors over a broad range of concentrations with a CI value of 0.7. Conclusions: In this study, we present and discuss the initial proof-of-concept preclinical data for the effective anti-leukemic activity of menin inhibition against KMT2A-rearranged infant leukemia cells. Furthermore, the comprehensive drug screen and drug combination studies identified a spectrum of mechanistically-validated synergies, providing usable data for the formulation of multi-agent clinical studies for this currently unmet need in pediatric oncology.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".