Assessment of the effect of KMT2E expression in Acute Myeloid Leukemia on the response to all trans-retinoic acid (ATRA) and SLIT2 treatment

• Grant number: 21/11568-4
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Start date: March 01, 2022
• End date: December 31, 2025
• Field of knowledge: Health Sciences - Medicine - Medical Clinics
• Principal Investigator: Eduardo Magalhães Rego
• Grantee: Luíse Araújo de Albuquerque Simões
• Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated research grant: 13/08135-2 - CTC - Center for Cell-Based Therapy, AP.CEPID
• Associated scholarship(s): 23/11309-4 - Assessment of the role of KMT2E in acute myeloid leukemia in the context of all trans retinoic acid, BE.EP.DD

Abstract

Acute Myeloid Leukemia (AML) is a genetically, epigenetically, and clinically heterogeneous group of clonal Bone Marrow (BM) diseases. Since its treatment has not undergone major changes in the last decades, long-term disease outcomes have not shown significant improvement over the years. Furthermore, the therapies currently used have high systemic toxicity, thus making it necessary to study treatments with fewer side effects. Rearrangements in the KMT2 (Lysine (k)-methyltransferase 2) genes are frequently observed in AML. Among these genes, KMT2E is distinct from the other KMT2 family members, due to its lack of intrinsic histone methyltransferase activity. Instead, KMT2E indirectly regulates the expression of histone-modifying enzymes. Within this context, our group investigated the role of KMT2E in Acute Promyelocytic Leukemia (APL), in which we observed that its overexpression was associated with an increased response to ATRA. This phenotype was also validated in AML cells, wherein we observed that KMT2E sensitizes leukemic cells to ATRA treatment, reducing cell proliferation in favor of differentiation, probably due to epigenetic reprogramming. Additionally, we observed that the embryogenic SLIT2 gene is frequently found to be hypermethylated in AML patients and that the treatment with its peptide can reduce cell proliferation. This phenomenon was also observed in cells that do not express their canonical receptors and that have rearrangements in KMT2 genes. Therefore, in this project, we aim to investigate the effects of non-cytotoxic treatments such as SLIT2 and ATRA in KMT2E cells in vitro and in vivo. The KMT2E gene will be overexpressed and silenced in AML cells and the influence of both treatments on cell proliferation, clonogenic capacity, cell cycle progression, and apoptosis induction will be assessed. Immunoprecipitation assay will be performed to identify the ligands and mechanism of action of both treatments, which will be validated. Moreover, the evaluation of this treatment will be performed in vivo. (AU)