High ME1 Expression Is a Molecular Predictor of Post-Transplant Survival of Patients with Acute Myeloid Leukemia

Autor(es)

Ortiz Rojas, Cesar Alexander ; Costa-Neto, Abel ; Pereira-Martins, Diego A. ; Le, Duy Minh ; Sternadt, Dominique ; Weinhaeuser, Isabel ; Huls, Gerwin ; Schuringa, Jan Jacob ; Magalhaes Rego, Eduardo

• Tipo de documento: Artigo Científico
• Fonte: CANCERS; v. 15, n. 1, p. 17-pg., 2023-01-01.

Resumo

Simple Summary Acute myeloid leukemia (AML) is a blood cancer caused by genetic aberrations acquired by bone marrow progenitor cells, impeding healthy hematopoiesis. While AML is a heterogenous disease and variable parameters can impact AML prognosis, the options for treatments remain limited. The first line of treatment continues to be chemotherapy, usually followed by a hematopoietic stem cell transplant (HSCT) obtained from a compatible healthy donor. Of those transplanted patients, only about 50-60% will be long-term survivors. Consequently, the identification of markers that may predict the resulting HSCT outcome is a medical need. To address this issue, we applied different mathematical models at diagnosis to the transcriptome of AML patients who were treated with standard chemotherapy and then subjected to HSCT, in order to uncover genes associated with the clinical outcome post-transplant. By doing so we identified the ME1 gene, whereby high expression of ME1 was associated with worse prognosis. Furthermore, ME1 expression was correlated with energetic processes related to oxidative phosphorylation. Our study reveals that ME1 is an important biomarker and a potential therapeutic target. Several laboratory and clinical variables have been reported to be associated with the outcome of intensive chemotherapy for acute myeloid leukemia (AML), but only a few have been tested in the context of hematopoietic stem cell transplant (HSCT). This study aimed to identify genes whose expression of AML at diagnosis were associated with survival after HSCT. For this purpose, three publicly available adult AML cohorts (TCGA, BeatAML, and HOVON), whose patients were treated with intensive chemotherapy and then subjected to allogeneic or autologous HSCT, were included in this study. After whole transcriptome analysis, we identified ME1 as the only gene whose high expression was associated with shorter survival in patients subjected to HSCT. In addition, the inclusion of ME1 expression was able to improve the European LeukemiaNet risk stratification. Pathways related to lipid biosynthesis, mainly fatty acids, and cholesterol were positively correlated with ME1 expression. Furthermore, ME1 expression was associated with an M2 macrophage-enriched microenvironment, mature AML blasts hierarchy, and oxidative phosphorylation metabolism. Therefore, ME1 expression can be used as biomarker of poor response to HSCT in AML. (AU)

• Processo FAPESP: 17/08430-5 - Deteção dos transcritos do gene TP73 na Leucemia Promielocítica Aguda e seu impacto no prognóstico e resposta terapêutica
• Beneficiário: César Alexander Ortiz Rojas
• Modalidade de apoio: Bolsas no Brasil - Doutorado Direto
• Processo FAPESP: 17/23117-1 - Avaliação da via TP53/TP73 na enxertia de células de leucemia promielocítica aguda em modelo de xenotransplante
• Beneficiário: Diego Antonio Pereira Martins
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 15/09228-0 - Detecção e estudo funcional de Macrofágos Associados a Tumor em um modelo transgênico de leucemia promielocítica aguda.
• Beneficiário: Isabel Weinhauser
• Modalidade de apoio: Bolsas no Brasil - Doutorado
• Processo FAPESP: 13/08135-2 - CTC - Centro de Terapia Celular
• Beneficiário: Dimas Tadeu Covas
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs