Abstract 5431: The mitochondrial protease, YME1L regulates interferon signaling and is essential for AML growth and differentiation

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.