The CNS microenvironment promotes leukemia cell survival by disrupting tumor suppression and cell cycle regulation in pediatric T-cell acute lymphoblastic leukemia

• Published in: Experimental cell research 2024-04, Vol.437 (2), p.114015-114015, Article 114015
• Main Authors: Enlund, Sabina, Sinha, Indranil, Neofytou, Christina, Amor, Amanda Ramilo, Papadakis, Konstantinos, Nilsson, Anna, Jiang, Qingfei, Hermanson, Ola, Holm, Frida
• Format: Article
• Language: English
• Subjects: Cell Cycle; Cell Survival; Child; CNS; Humans; Medicin och hälsovetenskap; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; Recurrence; Survival; T-ALL; T-Lymphocytes - metabolism; Tumor Microenvironment; Tumor suppression
• ISSN: 0014-4827; 1090-2422; 1090-2422
• DOI: 10.1016/j.yexcr.2024.114015

A major obstacle in improving survival in pediatric T-cell acute lymphoblastic leukemia is understanding how to predict and treat leukemia relapse in the CNS. Leukemia cells are capable of infiltrating and residing within the CNS, primarily the leptomeninges, where they interact with the microenvironment and remain sheltered from systemic treatment. These cells can survive in the CNS, by hijacking the microenvironment and disrupting normal functions, thus promoting malignant transformation. While the protective effects of the bone marrow niche have been widely studied, the mechanisms behind leukemia infiltration into the CNS and the role of the CNS niche in leukemia cell survival remain unknown. We identified a dysregulated gene expression profile in CNS infiltrated T-ALL and CNS relapse, promoting cell survival, chemoresistance, and disease progression. Furthermore, we discovered that interactions between leukemia cells and human meningeal cells induced epigenetic alterations, such as changes in histone modifications, including H3K36me3 levels. These findings are a step towards understanding the molecular mechanisms promoting leukemia cell survival in the CNS microenvironment. Our results highlight genetic and epigenetic alterations induced by interactions between leukemia cells and the CNS niche, which could potentially be utilized as biomarkers to predict CNS infiltration and CNS relapse. •A distinct gene signature in CNS relapse pediatric T-ALL patient samples.•Dysregulation of cell survival and proliferation in CNS relapsed T-ALL.•Regulation of tumor suppression and apoptosis by histone methyltransferase SETD2.•CNS co-culture inhibits tumor suppression and promotes T-ALL cell survival.•Induction of cell cycle arrest during methotrexate treatment in CNS co-culture.