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Identification and functional characterization of macrophages subpopulations associated with resistance to anthracycline and cytarabine in acute myeloid leukemia through single-cell multiomic analysis

Grant number: 23/02952-0
Support Opportunities:Scholarships in Brazil - Post-Doctoral
Effective date (Start): August 01, 2023
Effective date (End): July 31, 2025
Field of knowledge:Health Sciences - Medicine
Principal Investigator:Eduardo Magalhães Rego
Grantee:César Alexander Ortiz Rojas
Host Institution: Faculdade de Medicina (FM). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Adult acute myeloid leukemia (AML) patients who are considered eligible for intensive chemotherapy are treated with regimens that include anthracyclines and cytarabine (AraC), also known as 7+3. Clinical and genetic abnormalities are used to indicate the best therapy strategy, and more recently, are essential in selecting patients who will benefit from targeted therapies (e.g., FLT3 inhibitors). Despite recent progress, 10-20% of AML patients will be primary refractory, and another 30-50% will relapse after reaching complete remission (CR). Detection of Measurable Residual Disease (MRD) is a strong, independent prognostic marker of increased risk of relapse and shorter survival in patients with AML. The comparison of responders (MRD < 0.1%) and relapse-refractory (MRD > 0.1%) AML cases is a suitable strategy for the identification of factors associated with chemotherapy resistance. Thus, leukemic cell types and microenvironment components have demonstrated to be critical factors for leukemic progression. Recently, our group demonstrated that primary AML cells derived from bone marrow with high content of AML-associated macrophages (AAMs) display increased resistance to AraC. Also, we showed that AAMs are mainly immunosuppressive, and that their interaction with AML cells induce a reduction in the phagocytic activity, and support the growth of leukemic cells instead of destroying them. Although this offers therapeutic opportunities, the AAMs content is diverse, being necessary a fine characterization of macrophages subpopulations in the bone marrow of AML patients. Additionally, because our group has demonstrated that AML mutations, like FLT3-ITD or mutations in NPM1, could play a key role in the modulation of the macrophage's activity, studies considering other molecular and genetic alterations are necessary. In this project, we propose the study of AML bone marrow samples of patients with different chemotherapy response, assessed by MRD, through a multiomic approach that combine CITE-seq, a sequencing-based method that simultaneously quantifies cell surface protein and transcriptomic data within a single cell readout, with single-cell genotyping, to explore the AAMs subpopulations and their association with the therapeutic response.

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