Abstract 5431: The mitochondrial protease, YME1L regulates interferon signaling and is essential for AML growth and differentiation
Bibliographic record
Abstract
Yeast Mitochondrial Escape 1-Like 1 (YME1L) is an ATP-dependent metalloprotease located in the inner mitochondrial membrane. Here, we examined the expression and function of this protease in AML. YME1L protein was expressed in 6/7 tested AML cell lines. In 17 of 23 primary AML samples, YME1L protein was > 2-fold higher than normal hematopoietic cells. High YME1L mRNA expression was associated with lower five-year survival rates in AML patients.To assess the dependency of AML cells on this protease, we knocked down YME1L with shRNA in OCI-AML2, NB4, TEX, and THP-1 AML cell lines. YME1L knockdown reduced AML cell proliferation in these tested lines. In addition, the depletion of YME1L reduced the clonogenic growth of leukemia cells, and decreased the engraftment of AML cells into the marrow of immune-deficient NS-GF mice. Thus, YME1L is essential for AML cells and leukemia-initiating cells. To understand the mechanisms of action of this protease and the downstream consequences of its depletion, we measured changes in gene expression after the knockdown of YME1L in OCI-AML2 cells. By RNA sequencing, knockdown of YME1L upregulated genes associated with defense response to viruses, response to type I interferon, and type I interferon signaling pathways, consistent with viral mimicry and induction of interferon (IFN) signaling. Using real-time PCR we confirmed the importance of YME1L in regulating these pathways. Knockdown of YME1L upregulated the expression of beta and gamma IFN, as well as downstream interferon-stimulated genes ISG15, IFI44, and IFIT2. Upregulation of IFN pathways and induction of viral mimicry, can promote the differentiation of AML cells. Therefore, we assessed the differentiation of leukemic cells after the knockdown of YME1L. Knockdown of YME1L induced the differentiation of OCI-AML2 cells as evidenced by upregulation of CD14 protein expression.In summary, YME1L is overexpressed in a subset of AML cells. This protease is essential for AML cells and controls differentiation by regulating IFN and viral mimicry pathways. Citation Format: Yihe Zhang, Rose Hurren, Yongran Yan, Marcela Gronda, Dakai Ling, Karen Kai-Lin Fang, Andrea Arruda, Mark D. Minden, Aaron D. Schimmer. The mitochondrial protease, YME1L regulates interferon signaling and is essential for AML growth and differentiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5431.
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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 | 0.001 |
| 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".