Hoxa9 and Meis1 Cooperatively Induce Addiction to Syk Signaling By Suppression of Mir-146a in Acute Myeloid Leukemia
Bibliographic record
Abstract
Abstract Acute Myeloid Leukemia (AML) is driven by cell populations with stem cell-like characteristics, so called leukemia stem cells (LSC). The transcription factor Meis1 is one of the critical regulators of LSC and is capable to rapidly induce AML in murine models in the context of Hox gene overexpression. Despite sophisticated studies identifying Hox- and Meis1-regulated genes, the knowledge about their impact on intracellular signaling pathways and its functional consequences is still limited. Since Hox and Meis1 gene overexpression is often found in high risk AML and since both factors are currently considered as undruggable, we aimed to elucidate their role in regulating intracellular signaling and to investigate, if cells transformed by Hoxa9 and Meis1 are addicted to certain signaling processes. To characterize the effect of Meis1 in the context of Hox gene overexpression on protein expression and intracellular signaling, we have performed a comprehensive (phospho)proteomic analysis and correlated it with transcriptome sequencing data. Our analysis revealed that Meis1 upregulates expression of spleen tyrosine kinase (Syk) without affecting its mRNA expression level. This was confirmed in patient-derived AML cells. By global analysis of microRNA expression and subsequent functional analyses, we could identify the downregulation of miR-146a, which turned out to be PU.1-dependent, as a mediator for this post-transcriptional upregulation of SYK in Hoxa9/Meis1 overexpressing cells. To further investigate, if an activation of Syk signaling can mimic Meis1 in inducing leukemia in our murine AML transplantation model, we overexpressed Syk in Hoxa9-transformed myeloid progenitors and found that this resulted in an acceleration in leukemia development comparable to the acceleration observed upon combined Hoxa9/Meis1 overexpression. We also found that Syk overexpression resulted in an increased expression of Meis1 and an induction of Meis1-dependent gene expression signatures. Notably, Hoxa9/Meis1-transformed cells also exhibited a remarkable sensitivity to Syk inhibition and SYK knockdown in vitro and in vivo, while Hoxa9-transformed cells did not. In summary, we identified a previously unknown signaling loop between Meis1 overexpression and Syk signaling involving miR-146a as a regulator of SYK expression. Hence, we believe that Syk inhibition by small molecules might be a potential therapeutic option for AMLs particularly in the context of Hox/Meis1-overexpression. Disclosures Berg: Astellas: Other: Travel Funding; Alexion: Other: Travel Funding; Celgene: Other: Travel Funding.
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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".