High LETM1 Expression Associates with Impaired Mitophagy and Bad Prognosis in Diffuse Large B-cell Lymphomas and Acute Myeloid Leukemias

Leucine zipper-EF-hand containing transmembrane protein 1 (LETM1) is a mitochondrial inner membrane protein involved in mitochondrial morphology and homeostasis. LETM1 is highly expressed in many human solid cancers and correlates with poor prognosis possibly due to mitochondrial dysfunction. However, the functional role of LETM1 in the progression of hematological malignancies remains to be elucidated. In this study, we found that higher LETM1 expression was associated with a short overall survival in Diffuse Large B-Cell Lymphoma (DLBCL) and in Acute Myeloid Leukemias (AML) patients. The transcriptomic analysis showed that LETM1 expression is positively correlated with oncogenic pathways (e.g., glucose transport, stem cell maintenance, mTOR and Wnt signaling pathways, mitotic G2/M phase transition, and cell proliferation) and negatively correlated with autophagy-related processes and apoptosis. In contrast, low expression of LETM1 associated with upregulation of BECLIN-1-dependent mitophagy, which in turn improves the prognosis in both DLBCL and AML patients. Our data suggest that LETM1 is a valuable prognostic marker and a possible therapeutic target for improving the clinical outcome in hematological malignancies.