Transcriptional memory and drug resistance in pediatric Acute Lymphoblastic Leukemia

• Grant number: 24/03383-2
• Support Opportunities: Scholarships in Brazil - Master
• Start date: November 01, 2024
• End date: February 28, 2026
• Field of knowledge: Health Sciences - Medicine
• Principal Investigator: José Andrés Yunes
• Grantee: Manuella Munuera Hoff
• Host Institution: Centro Infantil de Investigações Hematológicas Dr Domingos A Boldrini (CIB). Campinas , SP, Brazil

Abstract

Acute lymphoid leukemia (ALL) is the main cancer affecting children. Despite the high cure rates achieved in recent decades, and even with great effort in the search for new therapeutic strategies, approximately 20 to 30% of cases relapse from the disease, due to resistance to chemotherapy. Although some genetic subgroups of ALL are associated with a peculiar drug resistance/sensitivity profile, it has been difficult to unravel and overcome the mechanisms of chemotherapy resistance. A recent study using single cell NGS showed that the evolution of the resistant clone does not occur through a process of Darwinian selection, in which chemotherapy would select a different genetic subclone that is more resistant to treatment. It has been discovered that ALL cells transit or are in different states of transcriptional profiles. Chemotherapy apparently selects cells in a pre-existing transcriptional state, characterized by low expression of the MYC and E2F pathways. It was also discovered that the cells selected under the action of chemotherapy show greater expression of EZH2 and DNMT3A/B, factors that act on histone and DNA methylation, respectively. These findings suggest that the evolution of drug resistance in ALL takes place at the transcriptional level and is then fixed by means of an epigenetic mechanism. Similar mechanisms have been described in other uni- and pluricellular organisms which, when challenged sequentially by some type of stress, respond in such a way that they reveal that they have acquired a "transcriptional memory" of it. In this project, we intend to generate relapses of ALL in mice, using diagnostic samples from 5 cases of ALL with a good clinical response and 5 cases of poorly responding ALL. The mice will be treated with a combination of vincristine (V), dexamethasone (X), l-asparaginase (L) and daunorubicin (D) for a limited period of time. Samples of "relapsed" ALL, i.e. that appear after the treatment blocks, will be collected and characterized for in vitro resistance to V, X, L and D. When increased resistance to one of the 4 chemotherapies is found, we will also test the resistance profile to 61 oncological drugs. The transcriptome of the relapse samples will be compared to that of matched control samples, i.e. the same ALL maintained in untreated mice. We will then compare the 5 good responders to the poor responders. We hope to characterize the transcriptional and pharmacological evolution of ALL in the face of chemotherapy, helping to determine whether there is transcriptional memory formation and whether this is greater or more frequent in poor responders, while at the same time we hope to characterize the transcriptomic profile of treatment resistance.